Low oxygen in vivo analyte sensor

ABSTRACT

The present invention relates generally to systems and methods for measuring an analyte in a host. More particularly, the present invention relates to systems and methods for transcutaneous and subcutaneous measurement of glucose in a host.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/333,837, filed Jan. 17, 2006, now U.S. Pat. No. 7,899,511. Thedisclosure of the foregoing application is hereby incorporated byreference in its entirety and is hereby made a portion of thisapplication.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods formeasuring an analyte in a host. More particularly, the present inventionrelates to systems and methods for transcutaneous and subcutaneousmeasurement of glucose in a host.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which can cause anarray of physiological derangements associated with the deterioration ofsmall blood vessels, for example, kidney failure, skin ulcers, orbleeding into the vitreous of the eye. A hypoglycemic reaction (lowblood sugar) can be induced by an inadvertent overdose of insulin, orafter a normal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a person with diabetes carries a self-monitoring bloodglucose (SMBG) monitor, which typically requires uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a personwith diabetes normally only measures his or her glucose levels two tofour times per day. Unfortunately, such time intervals are so far spreadapart that the person with diabetes likely finds out too late of ahyperglycemic or hypoglycemic condition, sometimes incurring dangerousside effects. It is not only unlikely that a person with diabetes willtake a timely SMBG value, it is also likely that he or she will not knowif his or her blood glucose value is going up (higher) or down (lower)based on conventional method. This inhibits the ability to make educatedinsulin therapy decisions.

SUMMARY OF THE INVENTION

Accordingly, in a first aspect a wholly implantable analyte sensorsystem is provided comprising a wholly implantable body comprising anelectrode configured to measure a glucose level in a host; a membranedisposed over the electrode and configured to limit transport of glucoseto the electrode; a layer comprising an enzyme to catalyze a reaction ofglucose and oxygen as a co-reactant; and a sensor electronics unitoperably connected to the electrode and configured to measure a currentproduced by the electrode, wherein the sensor electronics unit isconfigured to measure glucose concentration with substantial linearityat glucose concentrations of up to about 400 mg/dL at an oxygenconcentration of less than about 0.6 mg/L.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to directly measure the current produced by the electrode.

In an embodiment of the first aspect, the wholly implantable analytesensor system further comprises a biointerface membrane configured tosupport tissue ingrowth.

In an embodiment of the first aspect, the wholly implantable analytesensor system further comprises an analog-to-digital converterconfigured to translate the current into a digital signal.

In an embodiment of the first aspect, the electrode comprises an exposedelectroactive working electrode surface with a surface area of fromabout 0.00002 in² to about 0.0079 in².

In an embodiment of the first aspect, the membrane comprises aresistance domain configured to have a permeability ratio of at leastabout 50:1 of glucose to an interferant.

In an embodiment of the first aspect, the membrane comprises aresistance domain configured to have a permeability ratio of at leastabout 200:1 of glucose to an interferant.

In an embodiment of the first aspect, the sensor system is configured tohave, in operation, a sensitivity of from about 1 pA/mg/dL to about 100pA/mg/dL.

In an embodiment of the first aspect, the sensor system is configured tohave, in operation, a sensitivity of from about 5 pA/mg/dL to about 25pA/mg/dL.

In an embodiment of the first aspect, the sensor system is configured tohave, in operation, a sensitivity of from about 3.5 to about 7.5pA/mg/dL.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to measure glucose at an oxygen concentration of less thanabout 0.3 mg/L.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to measure glucose at an oxygen concentration of less thanabout 0.15 mg/L.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to measure glucose at an oxygen concentration of less thanabout 0.05 mg/L.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to measure glucose at an oxygen concentration of less thanabout 0.02 mg/L.

In a second aspect, a device for measuring a concentration of glucose ina biological fluid is provided, the device comprising a housingcomprising an electronic circuit and at least one electrode operativelyconnected to the electronic circuit, wherein the electrode is configuredto determine, in operation, a concentration of glucose in a biologicalsample; and a glucose determining apparatus operatively connected to theelectrode and comprising a membrane impregnated with an oxidase, whereinthe electronic circuit is configured to measure, in operation, a currentrepresentative of the concentration of glucose in the biological sample,wherein the glucose determining apparatus is configured to measureglucose concentration with substantial linearity at glucoseconcentrations of up to about 400 mg/dL at an oxygen concentration ofless than about 0.6 mg/L.

In an embodiment of the second aspect, the device further comprises asemipermeable film configured to maintain an aqueous layer at anelectrochemically reactive surface of the electrode. The permeabilityratio of the semipermeable film can be at least about 200:1 of glucoseto a co-reactant.

In an embodiment of the second aspect, the impregnated oxidase ispresent in an amount sufficient for a sensor life of at least about oneyear. The sensor can be configured to have an operable life implantedwithin a host of at least about one month, or at least about six months,or at least about one year.

In an embodiment of the second aspect, the sensor system is configuredto have, in operation, a sensitivity of from about 5.0 pA/mg/dL to about10.0 pA/mg/dL.

In an embodiment of the second aspect, the sensor system is configuredto have, in operation, a sensitivity of about 7.5 pA/mg/dL.

In an embodiment of the second aspect, the device further comprises aporous outer layer configured for tissue ingrowth.

In an embodiment of the second aspect, the device is configured tomeasure glucose at an oxygen concentration of less than about 0.3 mg/L.

In an embodiment of the second aspect, the device is configured tomeasure glucose at an oxygen concentration of less than about 0.15 mg/L.

In an embodiment of the second aspect, the device is configured tomeasure glucose at an oxygen concentration of less than about 0.05 mg/L.

In an embodiment of the second aspect, the device is configured tomeasure glucose at an oxygen concentration of less than about 0.02 mg/L.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a transcutaneous analyte sensor system,including an applicator, a mounting unit, and an electronics unit.

FIG. 2 is a perspective view of a mounting unit, including theelectronics unit in its functional position.

FIG. 3 is an exploded perspective view of a mounting unit, showing itsindividual components.

FIG. 4 is an exploded perspective view of a contact subassembly, showingits individual components.

FIG. 5A is an expanded cutaway view of a proximal portion of a sensor.

FIG. 5B is an expanded cutaway view of a distal portion of a sensor.

FIG. 5C is a cross-sectional view through the sensor of FIG. 5B on lineC-C, showing an exposed electroactive surface of a working electrodesurrounded by a membrane system.

FIG. 6 is an exploded side view of an applicator, showing the componentsthat facilitate sensor insertion and subsequent needle retraction.

FIGS. 7A to 7D are schematic side cross-sectional views that illustrateapplicator components and their cooperating relationships.

FIG. 8A is a side view of an applicator matingly engaged to a mountingunit, prior to sensor insertion.

FIG. 8B is a side view of a mounting unit and applicator depicted in theembodiment of FIG. 8A, after the plunger subassembly has been pushed,extending the needle and sensor from the mounting unit.

FIG. 8C is a side view of a mounting unit and applicator depicted in theembodiment of FIG. 8A after the guide tube subassembly has beenretracted, retracting the needle back into the applicator.

FIGS. 9A to 9C are side views of an applicator and mounting unit,showing stages of sensor insertion.

FIGS. 10A and 10B are perspective and side cross-sectional views,respectively, of a sensor system showing the mounting unit immediatelyfollowing sensor insertion and release of the applicator from themounting unit.

FIGS. 11A and 11B are perspective and side cross-sectional views,respectively, of a sensor system showing the mounting unit afterpivoting the contact subassembly to its functional position.

FIGS. 12A to 12C are perspective and side views, respectively, of thesensor system showing the sensor, mounting unit, and electronics unit intheir functional positions.

FIG. 13 is a block diagram that illustrates electronics associated witha sensor system.

FIG. 14 is a perspective view of a sensor system wirelesslycommunicating with a receiver.

FIG. 15A is a block diagram that illustrates a configuration of amedical device including a continuous analyte sensor, a receiver, and anexternal device.

FIGS. 15B to 15D are illustrations of receiver liquid crystal displaysshowing embodiments of screen displays.

FIG. 16A is a flow chart that illustrates the initial calibration anddata output of sensor data.

FIG. 16B is a graph that illustrates one example of using priorinformation for slope and baseline.

FIG. 17 is a flow chart that illustrates evaluation of reference and/orsensor data for statistical, clinical, and/or physiologicalacceptability.

FIG. 18 is a flow chart that illustrates evaluation of calibrated sensordata for aberrant values.

FIG. 19 is a flow chart that illustrates self-diagnostics of sensordata.

FIG. 20 is an exploded perspective view of a wholly implantable analytesensor.

FIG. 21 is a circuit diagram of a potentiostat configured to control athree-electrode system described with reference to FIG. 20.

FIG. 22 is a cross-sectional schematic view of a biointerface membranein vivo in one embodiment, wherein the membrane comprises a celldisruptive domain and cell impermeable domain.

FIG. 23 is a cross-sectional schematic view of a biointerface membranein vivo in one embodiment, wherein the membrane comprises a celldisruptive domain and cell impermeable domain.

FIG. 24 is an illustration of the membrane of FIG. 23, showingcontractile forces caused by the fibrous tissue of the foreign bodyresponse (FBR).

FIGS. 25A and 25B are graphical representations of glucose sensor datain a human obtained over approximately three days.

FIG. 26A graphically depicts glucose levels as a function of the numberof days post-implant.

FIG. 26B graphically depicts a correlation plot (days 21 to 62) of aglucose infusion study with one device of a preferred embodiment.

FIG. 27 depicts a typical response to in vitro calibration to glucose ofa device of a preferred embodiment.

FIGS. 28A and 28B are graphical representations of glucose sensor datain a human obtained over approximately three days.

FIG. 29 is a plot showing functionality of a sensor of a preferredembodiment as a function of O₂ in a solution of 400 mg/L of glucose.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

Definitions

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a substance or chemicalconstituent in a biological fluid (for example, blood, interstitialfluid, cerebral spinal fluid, lymph fluid or urine) that can beanalyzed. Analytes can include naturally occurring substances,artificial substances, metabolites, and/or reaction products. In someembodiments, the analyte for measurement by the sensing regions,devices, and methods is glucose. However, other analytes arecontemplated as well, including but not limited to acarboxyprothrombin;acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase;albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-βhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A,hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F,D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocytearginase; erythrocyte protoporphyrin; esterase D; fattyacids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenyloin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), histamine, and5-hydroxyindoleacetic acid (FHIAA).

The term “host” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to mammals, particularly humans.

The term “exit-site” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the area where a medical device(for example, a sensor and/or needle) exits from the host's body.

The term “continuous (or continual) analyte sensing” as used herein is abroad term and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and furthermore refers withoutlimitation to the period in which monitoring of analyte concentration iscontinuously, continually, and or intermittently (regularly orirregularly) performed, for example, about every 5 to 10 minutes.

The term “electrochemically reactive surface” as used herein is a broadterm and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to thesurface of an electrode where an electrochemical reaction takes place.For example, a working electrode measures hydrogen peroxide produced bythe enzyme-catalyzed reaction of the analyte detected, which reacts tocreate an electric current. Glucose analyte can be detected utilizingglucose oxidase, which produces H₂O₂ as a byproduct. H₂O₂ reacts withthe surface of the working electrode, producing two protons (2H⁺), twoelectrons (2e⁻) and one molecule of oxygen (O₂), which produces theelectronic current being detected.

The term “electronic connection” as used herein is a broad term and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to any electronicconnection known to those in the art that can be utilized to interfacethe sensing region electrodes with the electronic circuitry of a device,such as mechanical (for example, pin and socket) or soldered electronicconnections.

The terms “interferant” and “interferants” as used herein are broadterms and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto species that interfere with the measurement of an analyte of interestin a sensor to produce a signal that does not accurately represent theanalyte measurement. In one example of an electrochemical sensor,interferants are compounds with oxidation potentials that overlap withthe analyte to be measured.

The term “sensing region” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to the region of amonitoring device responsible for the detection of a particular analyte.The sensing region generally comprises a non-conductive body, a workingelectrode (anode), a reference electrode (optional), and/or a counterelectrode (cathode) passing through and secured within the body formingelectrochemically reactive surfaces on the body and an electronicconnective means at another location on the body, and a multi-domainmembrane affixed to the body and covering the electrochemically reactivesurface.

The term “high oxygen solubility domain” as used herein is a broad termand is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to adomain composed of a material that has higher oxygen solubility thanaqueous media such that it concentrates oxygen from the biological fluidsurrounding the membrane system. The domain can act as an oxygenreservoir during times of minimal oxygen need and has the capacity toprovide, on demand, a higher oxygen gradient to facilitate oxygentransport across the membrane. Thus, the ability of the high oxygensolubility domain to supply a higher flux of oxygen to critical domainswhen needed can improve overall sensor function.

The term “domain” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a region of the membrane systemthat can be a layer, a uniform or non-uniform gradient (for example, ananisotropic region of a membrane), or a portion of a membrane.

The phrase “distal to” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. In general, the term indicates an element is locatedrelatively far from the reference point than another element.

The term “proximal to” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. In general, the term indicates an element is locatedrelatively near to the reference point than another element.

The terms “in vivo portion” and “distal portion” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto the portion of the device (for example, a sensor) adapted forinsertion into and/or existence within a living body of a host.

The terms “ex vivo portion” and “proximal portion” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto the portion of the device (for example, a sensor) adapted to remainand/or exist outside of a living body of a host.

The terms “raw data stream” and “data stream” as used herein are broadterms and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto an analog or digital signal from the analyte sensor directly relatedto the measured analyte. For example, the raw data stream is digitaldata in “counts” converted by an A/D converter from an analog signal(for example, voltage or amps) representative of an analyteconcentration. The terms broadly encompass a plurality of time spaceddata points from a substantially continuous analyte sensor, each ofwhich comprises individual measurements taken at time intervals rangingfrom fractions of a second up to, for example, 1, 2, or 5 minutes orlonger.

The term “count” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a unit of measurement of adigital signal. For example, a raw data stream measured in counts isdirectly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode.

The term “physiologically feasible” as used herein is a broad term andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and furthermore refers without limitation to one ormore physiological parameters obtained from continuous studies ofglucose data in humans and/or animals. For example, a maximal sustainedrate of change of glucose in humans of about 4 to 6 mg/dL/min and amaximum acceleration of the rate of change of about 0.1 to 0.2mg/dL/min/min are deemed physiologically feasible limits. Values outsideof these limits are considered non-physiological and are likely a resultof, e.g., signal error.

The term “ischemia” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to local and temporary deficiencyof blood supply due to obstruction of circulation to a part (forexample, a sensor). Ischemia can be caused, for example, by mechanicalobstruction (for example, arterial narrowing or disruption) of the bloodsupply.

The term “matched data pairs” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to reference data(for example, one or more reference analyte data points) matched withsubstantially time corresponding sensor data (for example, one or moresensor data points).

The term “Clarke Error Grid” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to an error gridanalysis, for example, an error grid analysis used to evaluate theclinical significance of the difference between a reference glucosevalue and a sensor generated glucose value, taking into account 1) thevalue of the reference glucose measurement, 2) the value of the sensorglucose measurement, 3) the relative difference between the two values,and 4) the clinical significance of this difference. See Clarke et al.,“Evaluating Clinical Accuracy of Systems for Self-Monitoring of BloodGlucose”, Diabetes Care, Volume 10, Number 5, September-October 1987,the contents of which are hereby incorporated by reference herein intheir entirety and are hereby made a part of this specification.

The term “Consensus Error Grid” as used herein is a broad term and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to an error gridanalysis that assigns a specific level of clinical risk to any possibleerror between two time corresponding measurements, e.g., glucosemeasurements. The Consensus Error Grid is divided into zones signifyingthe degree of risk posed by the deviation. See Parkes et al., “A NewConsensus Error Grid to Evaluate the Clinical Significance ofInaccuracies in the Measurement of Blood Glucose”, Diabetes Care, Volume23, Number 8, August 2000, the contents of which are hereby incorporatedby reference herein in their entirety and are hereby made a part of thisspecification.

The term “clinical acceptability” as used herein is a broad term and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to determination ofthe risk of an inaccuracy to a patient. Clinical acceptability considersa deviation between time corresponding analyte measurements (forexample, data from a glucose sensor and data from a reference glucosemonitor) and the risk (for example, to the decision making of a personwith diabetes) associated with that deviation based on the analyte valueindicated by the sensor and/or reference data. An example of clinicalacceptability can be 85% of a given set of measured analyte valueswithin the “A” and “B” region of a standard Clarke Error Grid when thesensor measurements are compared to a standard reference measurement.

The term “sensor” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the component or region of adevice by which an analyte can be quantified.

The term “needle” as used herein is a broad term and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a slender hollow instrument forintroducing material into or removing material from the body.

The terms “operably connected” and “operably linked” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto one or more components linked to one or more other components. Theterms can refer to a mechanical connection, an electrical connection, ora connection that allows transmission of signals between the components.For example, one or more electrodes can be used to detect the amount ofanalyte in a sample and to convert that information into a signal; thesignal can then be transmitted to a circuit. In such an example, theelectrode is “operably linked” to the electronic circuitry.

The term “baseline” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the component of an analytesensor signal that is not related to the analyte concentration. In oneexample of a glucose sensor, the baseline is composed substantially ofsignal contribution due to factors other than glucose (for example,interfering species, non-reaction-related hydrogen peroxide, or otherelectroactive species with an oxidation potential that overlaps withhydrogen peroxide). In some embodiments wherein a calibration is definedby solving for the equation y=mx+b, the value of b represents thebaseline of the signal.

The terms “sensitivity” and “slope” as used herein are broad terms andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and furthermore refer without limitation to anamount of electrical current produced by a predetermined amount (unit)of the measured analyte. For example, in one preferred embodiment, asensor has a sensitivity (or slope) of about 3.5 to about 7.5 picoAmpsof current for every 1 mg/dL of glucose analyte. Sensitivitymeasurements are typically obtained in vitro (e.g., a calibration checkduring manufacture). The sensors of preferred embodiments typicallyexhibit a sensitivity in vitro of from about 5 to about 25 pA/mg/dL. Insome circumstances, in vitro sensitivity translates to a differentsensitivity (for the same sensor) when implanted in vivo. For example, asensor exhibiting a sensitivity of from 3.5 to 8 pA/mg/dL in vitro canexhibit a sensitivity in vivo of 3.5 to 20 pA/mg/dL.

The term “membrane system” as used herein is a broad term and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and furthermore refers without limitation to a permeable orsemi-permeable membrane that can be comprised of two or more domains andis typically constructed of materials of a few microns thickness ormore, which is permeable to oxygen and is optionally permeable to, e.g.,glucose or another analyte. In one example, the membrane systemcomprises an immobilized glucose oxidase enzyme, which enables areaction to occur between glucose and oxygen whereby a concentration ofglucose can be measured.

The terms “processor module” and “microprocessor” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto a computer system, state machine, processor, or the like designed toperform arithmetic or logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The terms “smoothing” and “filtering” as used herein are broad terms andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and furthermore refer without limitation tomodification of a set of data to make it smoother and more continuous orto remove or diminish outlying points, for example, by performing amoving average of the raw data stream.

The term “algorithm” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to a computational process (forexample, programs) involved in transforming information from one stateto another, for example, by using computer processing.

The term “regression” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to finding a line for which a setof data has a minimal measurement (for example, deviation) from thatline. Regression can be linear, non-linear, first order, second order,or the like. One example of regression is least squares regression.

The term “calibration” as used herein is a broad term and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andfurthermore refers without limitation to the process of determining therelationship between the sensor data and the corresponding referencedata, which can be used to convert sensor data into meaningful valuessubstantially equivalent to the reference data. In some embodiments,namely, in continuous analyte sensors, calibration can be updated orrecalibrated over time as changes in the relationship between the sensordata and reference data occur, for example, due to changes insensitivity, baseline, transport, metabolism, or the like.

The terms “interferants” and “interfering species” as used herein arebroad terms and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and furthermore refer without limitationto effects and/or species that interfere with the measurement of ananalyte of interest in a sensor to produce a signal that does notaccurately represent the analyte concentration. In one example of anelectrochemical sensor, interfering species are compounds with anoxidation potential that overlap that of the analyte to be measured,thereby producing a false positive signal.

Sensor System

Analyte sensors, including but not limited to transcutaneous analytesensors and wholly implantable (e.g., subcutaneous) analyte sensors, areprovided. A transcutaneous analyte sensor system is provided thatincludes an applicator for inserting the transdermal analyte sensorunder a host's skin. The sensor system includes a sensor for sensing theanalyte, wherein the sensor is associated with a mounting unit adaptedfor mounting on the skin of the host. The mounting unit houses theelectronics unit associated with the sensor and is adapted for fasteningto the host's skin. In certain embodiments, the system further includesa receiver for receiving and/or processing sensor data.

FIG. 1 is a perspective view of a transcutaneous analyte sensor system10. In the preferred embodiment of a system as depicted in FIG. 1, thesensor includes an applicator 12, a mounting unit 14, and an electronicsunit 16. The system can further include a receiver 158, such as isdescribed in more detail with reference to FIG. 14.

The mounting unit 14 includes a base 24 adapted for mounting on the skinof a host, a sensor adapted for transdermal insertion through the skinof a host (see FIG. 4), and one or more contacts 28 configured toprovide secure electrical contact between the sensor and the electronicsunit 16. The mounting unit 14 is designed to maintain the integrity ofthe sensor in the host so as to reduce or eliminate translation ofmotion between the mounting unit, the host, and/or the sensor.

In one embodiment, an applicator 12 is provided for inserting the sensor32 through the host's skin at the appropriate insertion angle with theaid of a needle (see FIGS. 6 through 8), and for subsequent removal ofthe needle using a continuous push-pull action. Preferably, theapplicator comprises an applicator body 18 that guides the applicatorcomponents (see FIGS. 6 through 8) and includes an applicator body base60 configured to mate with the mounting unit 14 during insertion of thesensor into the host. The mate between the applicator body base 60 andthe mounting unit 14 can use any known mating configuration, forexample, a snap-fit, a press-fit, an interference-fit, or the like, todiscourage separation during use. One or more release latches 30 enablerelease of the applicator body base 60, for example, when the applicatorbody base 60 is snap fit into the mounting unit 14.

The electronics unit 16 includes hardware, firmware, and/or softwarethat enable measurement of levels of the analyte via the sensor. Forexample, the electronics unit 16 can comprise a potentiostat, a powersource for providing power to the sensor, other components useful forsignal processing, and preferably an RF module for transmitting datafrom the electronics unit 16 to a receiver (see FIGS. 13 to 15).Electronics can be affixed to a printed circuit board (PCB), or thelike, and can take a variety of forms. For example, the electronics cantake the form of an integrated circuit (IC), such as anApplication-Specific Integrated Circuit (ASIC), a microcontroller, or aprocessor. Preferably, electronics unit 16 houses the sensorelectronics, which comprise systems and methods for processing sensoranalyte data. Examples of systems and methods for processing sensoranalyte data are described in more detail below and in co-pending U.S.application Ser. No. 10/633,367 filed Aug. 1, 2003, and entitled,“SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA.”

After insertion of the sensor using the applicator 12, and subsequentrelease of the applicator 12 from the mounting unit 14 (see FIGS. 8A to8C), the electronics unit 16 is configured to releasably mate with themounting unit 14 in a manner similar to that described above withreference to the applicator body base 60. The electronics unit 16includes contacts on its backside (not shown) configured to electricallyconnect with the contacts 28, such as are described in more detail withreference to FIGS. 2 through 4. In one embodiment, the electronics unit16 is configured with programming, for example initialization,calibration reset, failure testing, or the like, each time it isinitially inserted into the mounting unit 14 and/or each time itinitially communicates with the sensor 32.

Mounting Unit

FIG. 2 is a perspective view of a sensor system of a preferredembodiment, shown in its functional position, including a mounting unitand an electronics unit matingly engaged therein. FIGS. 8 to 10illustrate the sensor is its functional position for measurement of ananalyte concentration in a host.

In preferred embodiments, the mounting unit 14, also referred to as ahousing, comprises a base 24 adapted for fastening to a host's skin. Thebase can be formed from a variety of hard or soft materials, andpreferably comprises a low profile for minimizing protrusion of thedevice from the host during use. In some embodiments, the base 24 isformed at least partially from a flexible material, which is believed toprovide numerous advantages over conventional transcutaneous sensors,which, unfortunately, can suffer from motion-related artifactsassociated with the host's movement when the host is using the device.For example, when a transcutaneous analyte sensor is inserted into thehost, various movements of the sensor (for example, relative movementbetween the in vivo portion and the ex vivo portion, movement of theskin, and/or movement within the host (dermis or subcutaneous)) createstresses on the device and can produce noise in the sensor signal. It isbelieved that even small movements of the skin can translate todiscomfort and/or motion-related artifact, which can be reduced orobviated by a flexible or articulated base. Thus, by providingflexibility and/or articulation of the device against the host's skin,better conformity of the sensor system 10 to the regular use andmovements of the host can be achieved. Flexibility or articulation isbelieved to increase adhesion (with the use of an adhesive pad) of themounting unit 14 onto the skin, thereby decreasing motion-relatedartifact that can otherwise translate from the host's movements andreduced sensor performance.

FIG. 3 is an exploded perspective view of a sensor system of a preferredembodiment, showing a mounting unit, an associated contact subassembly,and an electronics unit. In some embodiments, the contacts 28 aremounted on or in a subassembly hereinafter referred to as a contactsubassembly 26 (see FIG. 4), which includes a contact holder 34configured to fit within the base 24 of the mounting unit 14 and a hinge38 that allows the contact subassembly 26 to pivot between a firstposition (for insertion) and a second position (for use) relative to themounting unit 14, which is described in more detail with reference toFIGS. 10 and 11. The term “hinge” as used herein is a broad term and isused in its ordinary sense, including, without limitation, to refer toany of a variety of pivoting, articulating, and/or hinging mechanisms,such as an adhesive hinge, a sliding joint, and the like; the term hingedoes not necessarily imply a fulcrum or fixed point about which thearticulation occurs.

In certain embodiments, the mounting unit 14 is provided with anadhesive pad 8, preferably disposed on the mounting unit's back surfaceand preferably including a releasable backing layer 9. Thus, removingthe backing layer 9 and pressing the base portion 24 of the mountingunit onto the host's skin adheres the mounting unit 14 to the host'sskin. Additionally or alternatively, an adhesive pad can be placed oversome or all of the sensor system after sensor insertion is complete toensure adhesion, and optionally to ensure an airtight seal or watertightseal around the wound exit-site (or sensor insertion site) (not shown).Appropriate adhesive pads can be chosen and designed to stretch,elongate, conform to, and/or aerate the region (e.g., the host's skin).

In preferred embodiments, the adhesive pad 8 is formed from spun-laced,open- or closed-cell foam, and/or non-woven fibers, and includes anadhesive disposed thereon, however a variety of adhesive padsappropriate for adhesion to the host's skin can be used, as isappreciated by one skilled in the art of medical adhesive pads. In someembodiments, a double-sided adhesive pad is used to adhere the mountingunit to the host's skin. In other embodiments, the adhesive pad includesa foam layer, for example, a layer wherein the foam is disposed betweenthe adhesive pad's side edges and acts as a shock absorber.

In some embodiments, the surface area of the adhesive pad 8 is greaterthan the surface area of the mounting unit's back surface.Alternatively, the adhesive pad can be sized with substantially the samesurface area as the back surface of the base portion. Preferably, theadhesive pad has a surface area on the side to be mounted on the host'sskin that is greater than about 1, 1.25, 1.5, 1.75, 2, 2.25, or 2.5,times the surface area of the back surface 25 of the mounting unit base24. Such a greater surface area can increase adhesion between themounting unit and the host's skin, minimize movement between themounting unit and the host's skin, and/or protect the wound exit-site(sensor insertion site) from environmental and/or biologicalcontamination. In some alternative embodiments, however, the adhesivepad can be smaller in surface area than the back surface assuming asufficient adhesion can be accomplished.

In some embodiments, the adhesive pad 8 is substantially the same shapeas the back surface 25 of the base 24, although other shapes can also beadvantageously employed, for example, butterfly-shaped, round, square,or rectangular. The adhesive pad backing can be designed for two-steprelease, for example, a primary release wherein only a portion of theadhesive pad is initially exposed to allow adjustable positioning of thedevice, and a secondary release wherein the remaining adhesive pad islater exposed to firmly and securely adhere the device to the host'sskin once appropriately positioned. The adhesive pad is preferablywaterproof. Preferably, a stretch-release adhesive pad is provided onthe back surface of the base portion to enable easy release from thehost's skin at the end of the useable life of the sensor, as isdescribed in more detail with reference to FIGS. 9A to 9C.

In some circumstances, it has been found that a conventional bondbetween the adhesive pad and the mounting unit may not be sufficient,for example, due to humidity that can cause release of the adhesive padfrom the mounting unit. Accordingly, in some embodiments, the adhesivepad can be bonded using a bonding agent activated by or accelerated byan ultraviolet, acoustic, radio frequency, or humidity cure. In someembodiments, a eutectic bond of first and second composite materials canform a strong adhesion. In some embodiments, the surface of the mountingunit can be pretreated utilizing ozone, plasma, chemicals, or the like,in order to enhance the bondability of the surface.

A bioactive agent is preferably applied locally at the insertion siteprior to or during sensor insertion. Suitable bioactive agents includethose which are known to discourage or prevent bacterial growth andinfection, for example, anti-inflammatory agents, antimicrobials,antibiotics, or the like. It is believed that the diffusion or presenceof a bioactive agent can aid in prevention or elimination of bacteriaadjacent to the exit-site. Additionally or alternatively, the bioactiveagent can be integral with or coated on the adhesive pad, or nobioactive agent at all is employed

FIG. 4 is an exploded perspective view of the contact subassembly 26 inone embodiment, showing its individual components. Preferably, awatertight (waterproof or water-resistant) sealing member 36, alsoreferred to as a sealing material, fits within a contact holder 34 andprovides a watertight seal configured to surround the electricalconnection at the electrode terminals within the mounting unit in orderto protect the electrodes (and the respective operable connection withthe contacts of the electronics unit 16) from damage due to moisture,humidity, dirt, and other external environmental factors. In oneembodiment, the sealing member 36 is formed from an elastomericmaterial, such as silicone; however, a variety of other elastomeric orsealing materials can also be used. In alternative embodiments, the sealis designed to form an interference fit with the electronics unit andcan be formed from a variety of materials, for example, flexibleplastics or noble metals. One of ordinary skill in the art appreciatesthat a variety of designs can be employed to provide a seal surroundingthe electrical contacts described herein. For example, the contactholder 34 can be integrally designed as a part of the mounting unit,rather than as a separate piece thereof. Additionally or alternatively,a sealant can be provided in or around the sensor (e.g., within or onthe contact subassembly or sealing member), such as is described in moredetail with reference to FIGS. 11A and 11B.

In the illustrated embodiment, the sealing member 36 is formed with araised portion 37 surrounding the contacts 28. The raised portion 37enhances the interference fit surrounding the contacts 28 when theelectronics unit 16 is mated to the mounting unit 14. Namely, the raisedportion surrounds each contact and presses against the electronics unit16 to form a tight seal around the electronics unit.

Contacts 28 fit within the seal 36 and provide for electrical connectionbetween the sensor 32 and the electronics unit 16. In general, thecontacts are designed to ensure a stable mechanical and electricalconnection of the electrodes that form the sensor 32 (see FIG. 5A to 5C)to mutually engaging contacts 28 thereon. A stable connection can beprovided using a variety of known methods, for example, domed metalliccontacts, cantilevered fingers, pogo pins, or the like, as isappreciated by one skilled in the art.

In preferred embodiments, the contacts 28 are formed from a conductiveelastomeric material, such as a carbon black elastomer, through whichthe sensor 32 extends (see FIGS. 10B and 11B). Conductive elastomers areadvantageously employed because their resilient properties create anatural compression against mutually engaging contacts, forming a securepress fit therewith. In some embodiments, conductive elastomers can bemolded in such a way that pressing the elastomer against the adjacentcontact performs a wiping action on the surface of the contact, therebycreating a cleaning action during initial connection. Additionally, inpreferred embodiments, the sensor 32 extends through the contacts 28wherein the sensor is electrically and mechanically secure by therelaxation of elastomer around the sensor (see FIGS. 7A to 7D).

In an alternative embodiment, a conductive, stiff plastic forms thecontacts, which are shaped to comply upon application of pressure (forexample, a leaf-spring shape). Contacts of such a configuration can beused instead of a metallic spring, for example, and advantageously avoidthe need for crimping or soldering through compliant materials;additionally, a wiping action can be incorporated into the design toremove contaminants from the surfaces during connection. Non-metalliccontacts can be advantageous because of their seamlessmanufacturability, robustness to thermal compression, non-corrosivesurfaces, and native resistance to electrostatic discharge (ESD) damagedue to their higher-than-metal resistance.

Sensor

Preferably, the sensor 32 includes a distal portion 42, also referred toas the in vivo portion, adapted to extend out of the mounting unit forinsertion under the host's skin, and a proximal portion 40, alsoreferred to as an ex vivo portion, adapted to remain above the host'sskin after sensor insertion and to operably connect to the electronicsunit 16 via contacts 28. Preferably, the sensor 32 includes two or moreelectrodes: a working electrode 44 and at least one additionalelectrode, which can function as a counter electrode and/or referenceelectrode, hereinafter referred to as the reference electrode 46. Amembrane system is preferably deposited over the electrodes, such asdescribed in more detail with reference to FIGS. 5A to 5C, below.

FIG. 5A is an expanded cutaway view of a proximal portion 40 of thesensor in one embodiment, showing working and reference electrodes. Inthe illustrated embodiments, the working and reference electrodes 44, 46extend through the contacts 28 to form electrical connection therewith(see FIGS. 10B and 11B). Namely, the working electrode 44 is inelectrical contact with one of the contacts 28 and the referenceelectrode 46 is in electrical contact with the other contact 28, whichin turn provides for electrical connection with the electronics unit 16when it is mated with the mounting unit 14. Mutually engaging electricalcontacts permit operable connection of the sensor 32 to the electronicsunit 16 when connected to the mounting unit 14; however other methods ofelectrically connecting the electronics unit 16 to the sensor 32 arealso possible. In some alternative embodiments, for example, thereference electrode can be configured to extend from the sensor andconnect to a contact at another location on the mounting unit (e.g.,non-coaxially). Detachable connection between the mounting unit 14 andelectronics unit 16 provides improved manufacturability, namely, therelatively inexpensive mounting unit 14 can be disposed of whenreplacing the sensor system after its usable life, while the relativelymore expensive electronics unit 16 can be reused with multiple sensorsystems.

In alternative embodiments, the contacts 28 are formed into a variety ofalternative shapes and/or sizes. For example, the contacts 28 can bediscs, spheres, cuboids, and the like. Furthermore, the contacts 28 canbe designed to extend from the mounting unit in a manner that causes aninterference fit within a mating cavity or groove of the electronicsunit, forming a stable mechanical and electrical connection therewith.

FIG. 5B is an expanded cutaway view of a distal portion of the sensor inone embodiment, showing working and reference electrodes. In preferredembodiments, the sensor is formed from a working electrode 44 and areference electrode 46 helically wound around the working electrode 44.An insulator 45 is disposed between the working and reference electrodesto provide necessary electrical insulation there between. Certainportions of the electrodes are exposed to enable electrochemicalreaction thereon, for example, a window 43 can be formed in theinsulator to expose a portion of the working electrode 44 forelectrochemical reaction.

In preferred embodiments, each electrode is formed from a fine wire witha diameter of from about 0.001 or less to about 0.010 inches or more,for example, and is formed from, e.g., a plated insulator, a platedwire, or bulk electrically conductive material. Although the illustratedelectrode configuration and associated text describe one preferredmethod of forming a transcutaneous sensor, a variety of knowntranscutaneous sensor configurations can be employed with thetranscutaneous analyte sensor system of the preferred embodiments, suchas are described in U.S. Pat. No. 6,695,860 to Ward et al., U.S. Pat.No. 6,565,509 to Say et al., U.S. Pat. No. 6,248,067 to Causey III, etal., and U.S. Pat. No. 6,514,718 to Heller et al.

In preferred embodiments, the working electrode comprises a wire formedfrom a conductive material, such as platinum, platinum-iridium,palladium, graphite, gold, carbon, conductive polymer, alloys, or thelike. Although the electrodes can by formed by a variety ofmanufacturing techniques (bulk metal processing, deposition of metalonto a substrate, or the like), it can be advantageous to form theelectrodes from plated wire (e.g., platinum on steel wire) or bulk metal(e.g., platinum wire). It is believed that electrodes formed from bulkmetal wire provide superior performance (e.g., in contrast to depositedelectrodes), including increased stability of assay, simplifiedmanufacturability, resistance to contamination (e.g., which can beintroduced in deposition processes), and improved surface reaction(e.g., due to purity of material) without peeling or delamination.

The working electrode 44 is configured to measure the concentration ofan analyte. In an enzymatic electrochemical sensor for detectingglucose, for example, the working electrode measures the hydrogenperoxide produced by an enzyme catalyzed reaction of the analyte beingdetected and creates a measurable electronic current For example, in thedetection of glucose wherein glucose oxidase produces hydrogen peroxideas a byproduct, hydrogen peroxide reacts with the surface of the workingelectrode producing two protons (2H⁺), two electrons (2e⁻) and onemolecule of oxygen (O₂), which produces the electronic current beingdetected.

In preferred embodiments, the working electrode 44 is covered with aninsulating material 45, for example, a non-conductive polymer.Dip-coating, spray-coating, vapor-deposition, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode. In one embodiment, the insulating materialcomprises parylene, which can be an advantageous polymer coating for itsstrength, lubricity, and electrical insulation properties. Generally,parylene is produced by vapor deposition and polymerization ofpara-xylylene (or its substituted derivatives). However, any suitableinsulating material can be used, for example, fluorinated polymers,polyethyleneterephthalate, polyurethane, polyimide, other nonconductingpolymers, or the like. Glass or ceramic materials can also be employed.Other materials suitable for use include surface energy modified coatingsystems such as are marketed under the trade names AMC18, AMC148,AMC141, and AMC321 by Advanced Materials Components Express ofBellafonte, Pa. In some alternative embodiments, however, the workingelectrode may not require a coating of insulator.

The reference electrode 46, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, silver/silver chloride, or the like. Preferably, the referenceelectrode 46 is juxtapositioned and/or twisted with or around theworking electrode 44; however other configurations are also possible. Inthe illustrated embodiments, the reference electrode 46 is helicallywound around the working electrode 44. The assembly of wires is thenoptionally coated or adhered together with an insulating material,similar to that described above, so as to provide an insulatingattachment.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit), orthe like, to expose the electroactive surfaces. Alternatively, a portionof the electrode can be masked prior to depositing the insulator inorder to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g., a parylene coating without damaging, e.g., anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In the embodiment illustrated in FIG. 5B, a radial window 43 is formedthrough the insulating material 45 to expose a circumferentialelectroactive surface of the working electrode. Additionally, sections41 of electroactive surface of the reference electrode are exposed. Forexample, the 41 sections of electroactive surface can be masked duringdeposition of an outer insulating layer or etched after deposition of anouter insulating layer.

In some applications, cellular attack or migration of cells to thesensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g., as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some embodiments, the working electrode has a diameter of from about0.001 inches or less to about 0.010 inches or more, preferably fromabout 0.002 inches to about 0.008 inches, and more preferably from about0.004 inches to about 0.005 inches. The length of the window can be fromabout 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078inches) or more, and preferably from about 0.5 mm (about 0.02 inches) toabout 0.75 mm (0.03 inches). In such embodiments, the exposed surfacearea of the working electrode is preferably from about 0.000013 in²(0.0000839 cm²) or less to about 0.0025 in² (0.016129 cm²) or more(assuming a diameter of from about 0.001 inches to about 0.010 inchesand a length of from about 0.004 inches to about 0.078 inches). Thepreferred exposed surface area of the working electrode is selected toproduce an analyte signal with a current in the picoAmp range, such asis described in more detail elsewhere herein. However, a current in thepicoAmp range can be dependent upon a variety of factors, for examplethe electronic circuitry design (e.g., sample rate, current draw, A/Dconverter bit resolution, etc.), the membrane system (e.g., permeabilityof the analyte through the membrane system), and the exposed surfacearea of the working electrode. Accordingly, the exposed electroactiveworking electrode surface area can be selected to have a value greaterthan or less than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to optimize the signal-to-noise ratiowhile maintaining sensor performance in both high and low glucoseconcentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g., an electrode which can be used to generate oxygen,which is configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). Co-pending U.S. patentapplication Ser. No. 11/007,635, filed Dec. 7, 2004 and entitled“SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS” andU.S. patent application Ser. No. 11/004,561, filed Dec. 3, 2004 andentitled “CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR”describe some systems and methods for implementing and using additionalworking, counter, and/or reference electrodes. In one implementationwherein the sensor comprises two working electrodes, the two workingelectrodes are juxtapositioned (e.g., extend parallel to each other),around which the reference electrode is disposed (e.g., helicallywound). In some embodiments wherein two or more working electrodes areprovided, the working electrodes can be formed in a double-, triple-,quad-, etc. helix configuration along the length of the sensor (forexample, surrounding a reference electrode, insulated rod, or othersupport structure). The resulting electrode system can be configuredwith an appropriate membrane system, wherein the first working electrodeis configured to measure a first signal comprising glucose and baselineand the additional working electrode is configured to measure a baselinesignal consisting of baseline only (e.g., configured to be substantiallysimilar to the first working electrode without an enzyme disposedthereon.) In this way, the baseline signal can be subtracted from thefirst signal to produce a glucose-only signal that is substantially notsubject to fluctuations in the baseline and/or interfering species onthe signal.

Although the preferred embodiments illustrate one electrodeconfiguration including one bulk metal wire helically wound aroundanother bulk metal wire, other electrode configurations are alsocontemplated). In an alternative embodiment, the working electrodecomprises a tube with a reference electrode disposed or coiled inside,including an insulator there between. Alternatively, the referenceelectrode comprises a tube with a working electrode disposed or coiledinside, including an insulator there between. In another alternativeembodiment, a polymer (e.g., insulating) rod is provided, wherein theelectrodes are deposited (e.g., electro-plated) thereon. In yet anotheralternative embodiment, a metallic (e.g., steel) rod is provided, coatedwith an insulating material, onto which the working and referenceelectrodes are deposited. In yet another alternative embodiment, one ormore working electrodes are helically wound around a referenceelectrode.

Preferably, the electrodes and membrane systems of the preferredembodiments are coaxially formed, namely, the electrodes and/or membranesystem all share the same central axis. While not wishing to be bound bytheory, it is believed that a coaxial design of the sensor enables asymmetrical design without a preferred bend radius. Namely, in contrastto prior art sensors comprising a substantially planar configurationthat can suffer from regular bending about the plane of the sensor, thecoaxial design of the preferred embodiments do not have a preferred bendradius and therefore are not subject to regular bending about aparticular plane (which can cause fatigue failures and the like).However, non-coaxial sensors can be implemented with the sensor systemof the preferred embodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that the needle is able to insertthe sensor into the host and subsequently slide back over the sensor andrelease the sensor from the needle, without slots or other complexmulti-component designs.

In one such alternative embodiment, the two wires of the sensor are heldapart and configured for insertion into the host in proximal butseparate locations. The separation of the working and referenceelectrodes in such an embodiment can provide additional electrochemicalstability with simplified manufacture and electrical connectivity. It isappreciated by one skilled in the art that a variety of electrodeconfigurations can be implemented with the preferred embodiments.

Anchoring Mechanism

It is preferred that the sensor remains substantially stationary withinthe tissue of the host, such that migration or motion of the sensor withrespect to the surrounding tissue is minimized. Migration or motion isbelieved to cause inflammation at the sensor implant site due toirritation, and can also cause noise on the sensor signal due tomotion-related artifact, for example. Therefore, it can be advantageousto provide an anchoring mechanism that provides support for the sensor'sin vivo portion to avoid the above-mentioned problems. Combiningadvantageous sensor geometry with an advantageous anchoring minimizesadditional parts and allows for an optimally small or low profile designof the sensor. In one embodiment the sensor includes a surfacetopography, such as the helical surface topography provided by thereference electrode surrounding the working electrode. In alternativeembodiments, a surface topography could be provided by a roughenedsurface, porous surface (e.g. porous parylene), ridged surface, or thelike. Additionally (or alternatively), the anchoring can be provided byprongs, spines, barbs, wings, hooks, a bulbous portion (for example, atthe distal end), an S-bend along the sensor, a rough surface topography,a gradually changing diameter, combinations thereof, or the like, whichcan be used alone or in combination with the helical surface topographyto stabilize the sensor within the subcutaneous tissue.

Variable Stiffness

As described above, conventional transcutaneous devices are believed tosuffer from motion artifact associated with host movement when the hostis using the device. For example, when a transcutaneous analyte sensoris inserted into the host, various movements on the sensor (for example,relative movement within and between the subcutaneous space, dermis,skin, and external portions of the sensor) create stresses on thedevice, which is known to produce artifacts on the sensor signal.Accordingly, there are different design considerations (for example,stress considerations) on various sections of the sensor. For example,the distal portion 42 of the sensor can benefit in general from greaterflexibility as it encounters greater mechanical stresses caused bymovement of the tissue within the patient and relative movement betweenthe in vivo and ex vivo portions of the sensor. On the other hand, theproximal portion 40 of the sensor can benefit in general from a stiffer,more robust design to ensure structural integrity and/or reliableelectrical connections. Additionally, in some embodiments wherein aneedle is retracted over the proximal portion 40 of the device (seeFIGS. 6 to 8), a stiffer design can minimize crimping of the sensorand/or ease in retraction of the needle from the sensor. Thus, bydesigning greater flexibility into the in vivo (distal) portion 42, theflexibility is believed to compensate for patient movement, and noiseassociated therewith. By designing greater stiffness into the ex vivo(proximal) portion 40, column strength (for retraction of the needleover the sensor), electrical connections, and integrity can be enhanced.In some alternative embodiments, a stiffer distal end and/or a moreflexible proximal end can be advantageous as described in co-pendingU.S. patent application Ser. No. 11/077,759, filed Mar. 10, 2005, andentitled “TRANSCUTANEOUS MEDICAL DEVICE WITH VARIABLE STIFFNESS.”

The preferred embodiments provide a distal portion 42 of the sensor 32designed to be more flexible than a proximal portion 40 of the sensor.The variable stiffness of the preferred embodiments can be provided byvariable pitch of any one or more helically wound wires of the device,variable cross-section of any one or more wires of the device, and/orvariable hardening and/or softening of any one or more wires of thedevice, such as is described in more detail with reference to co-pendingU.S. patent application Ser. No. 11/077,759, filed Mar. 10, 2005, andentitled “TRANSCUTANEOUS MEDICAL DEVICE WITH VARIABLE STIFFNESS.”

Membrane System

FIG. 5C is a cross-sectional view through the sensor on line C-C of FIG.5B showing the exposed electroactive surface of the working electrodesurrounded by the membrane system in one embodiment. Preferably, amembrane system is deposited over at least a portion of theelectroactive surfaces of the sensor 32 (working electrode andoptionally reference electrode) and provides protection of the exposedelectrode surface from the biological environment, diffusion resistance(limitation) of the analyte if needed, a catalyst for enabling anenzymatic reaction, limitation or blocking of interferants, and/orhydrophilicity at the electrochemically reactive surfaces of the sensorinterface. Some examples of suitable membrane systems are described inco-pending U.S. patent application Ser. No. 10/838,912, filed May 3,2004, and entitled “IMPLANTABLE ANALYTE SENSOR.”

In general, the membrane system includes a plurality of domains, forexample, an electrode domain 47, an interference domain 48, an enzymedomain 49 (for example, including glucose oxidase), and a resistancedomain 50, and can include a high oxygen solubility domain, and/or abioprotective domain (not shown), such as is described in more detail inU.S. patent application Ser. No. 10/838,912, and such as is described inmore detail below. The membrane system can be deposited on the exposedelectroactive surfaces using known thin film techniques (for example,spraying, electro-depositing, dipping, or the like). In one embodiment,one or more domains are deposited by dipping the sensor into a solutionand drawing out the sensor at a speed that provides the appropriatedomain thickness. However, the membrane system can be disposed over (ordeposited on) the electroactive surfaces using any known method as willbe appreciated by one skilled in the art.

Electrode Domain

In some embodiments, the membrane system comprises an optional electrodedomain 47, also referred to as the electrolyte domain or electrolyte.The electrode domain 47 is provided to ensure that an electrochemicalreaction occurs between the electroactive surfaces of the workingelectrode and the reference electrode, and thus the electrode domain 47is preferably situated more proximal to the electroactive surfaces thanthe enzyme domain. Preferably, the electrode domain 47 includes asemipermeable coating that maintains a layer of water at theelectrochemically reactive surfaces of the sensor, for example, ahumectant in a binder material can be employed as an electrode domain;this allows for the full transport of ions in the aqueous environment.The electrode domain can also assist in stabilizing the operation of thesensor by overcoming electrode start-up and drifting problems caused byinadequate electrolyte. The material that forms the electrode domain canalso protect against pH-mediated damage that can result from theformation of a large pH gradient due to the electrochemical activity ofthe electrodes.

In one embodiment, the electrode domain 47 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 19.5 microns, and more preferably from about 2,2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dry film”thickness refers to the thickness of a cured film cast from a coatingformulation by standard coating techniques.

In certain embodiments, the electrode domain 47 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate functional groups and non-ionic hydrophilic polyethersegments, wherein the polyurethane polymer is crosslinked with a watersoluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

Preferably, the electrode domain 47 is deposited by spray or dip-coatingthe electroactive surfaces of the sensor 32. More preferably, theelectrode domain is formed by dip-coating the electroactive surfaces inan electrode solution and curing the domain for a time of from about 15to about 30 minutes at a temperature of from about 40 to about 55° C.(and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). Inembodiments wherein dip-coating is used to deposit the electrode domain,a preferred insertion rate of from about 1 to about 3 inches per minute,with a preferred dwell time of from about 0.5 to about 2 minutes, and apreferred withdrawal rate of from about 0.25 to about 2 inches perminute provide a functional coating. However, values outside of thoseset forth above can be acceptable or even desirable in certainembodiments, for example, dependent upon viscosity and surface tensionas is appreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes.

Although an independent electrode domain is described herein, in someembodiments, sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).

Interference Domain

In some embodiments, an optional interference domain 48 is provided,which generally includes a polymer domain that restricts the flow of oneor more interferants. In some embodiments, the interference domain 48functions as a molecular sieve that allows analytes and other substancesthat are to be measured by the electrodes to pass through, whilepreventing passage of other substances, including interferants such asascorbate and urea (see U.S. Pat. No. 6,001,067 to Shults). Some knowninterferants for a glucose-oxidase based electrochemical sensor includeacetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid.

Several polymer types that can be utilized as a base material for theinterference domain 48 include polyurethanes, polymers having pendantionic groups, and polymers having controlled pore size, for example. Inone embodiment, the interference domain includes a thin, hydrophobicmembrane that is non-swellable and restricts diffusion of low molecularweight species. The interference domain 48 is permeable to relativelylow molecular weight substances, such as hydrogen peroxide, butrestricts the passage of higher molecular weight substances, includingglucose and ascorbic acid. Other systems and methods for reducing oreliminating interference species that can be applied to the membranesystem of the preferred embodiments are described in co-pending U.S.patent application Ser. No. 10/896,312 filed Jul. 21, 2004 and entitled“ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS,” Ser. No. 10/991,353,filed Nov. 16, 2004 and entitled, “AFFINITY DOMAIN FOR AN ANALYTESENSOR,” Ser. No. 11/007,635, filed Dec. 7, 2004 and entitled “SYSTEMSAND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS” and Ser. No.11/004,561, filed Dec. 3, 2004 and entitled, “CALIBRATION TECHNIQUES FORA CONTINUOUS ANALYTE SENSOR.” In some alternative embodiments, adistinct interference domain is not included.

In preferred embodiments, the interference domain 48 is deposited ontothe electrode domain (or directly onto the electroactive surfaces when adistinct electrode domain is not included) for a domain thickness offrom about 0.05 micron or less to about 20 microns or more, morepreferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45,0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably fromabout 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. Thickermembranes can also be useful, but thinner membranes are generallypreferred because they have a lower impact on the rate of diffusion ofhydrogen peroxide from the enzyme membrane to the electrodes.Unfortunately, the thin thickness of the interference domainsconventionally used can introduce variability in the membrane systemprocessing. For example, if too much or too little interference domainis incorporated within a membrane system, the performance of themembrane can be adversely affected.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 49 disposed more distally situated from the electroactivesurfaces than the interference domain 48 (or electrode domain 47 when adistinct interference is not included). In some embodiments, the enzymedomain is directly deposited onto the electroactive surfaces (whenneither an electrode or interference domain is included). In thepreferred embodiments, the enzyme domain 49 provides an enzyme tocatalyze the reaction of the analyte and its co-reactant, as describedin more detail below. Preferably, the enzyme domain includes glucoseoxidase; however other oxidases, for example, galactose oxidase oruricase oxidase, can also be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain 49 is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See U.S. patent application Ser. No. 10/896,639 filed on Jul.21, 2004 and entitled “OXYGEN ENHANCING MEMBRANE SYSTEMS FOR IMPLANTABLEDEVICE.”

In preferred embodiments, the enzyme domain 49 is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 toabout 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5microns, and more preferably from about 2, 2.5 or 3 microns to about3.5, 4, 4.5, or 5 microns. However in some embodiments, the enzymedomain is deposited onto the electrode domain or directly onto theelectroactive surfaces. Preferably, the enzyme domain 49 is deposited byspray or dip coating. More preferably, the enzyme domain is formed bydip-coating the electrode domain into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40 to about 55° C. (and can be accomplished under vacuum(e.g., 20 to 30 mmHg)). In embodiments wherein dip-coating is used todeposit the enzyme domain at room temperature, a preferred insertionrate of from about 1 inch per minute to about 3 inches per minute, witha preferred dwell time of from about 0.5 minutes to about 2 minutes, anda preferred withdrawal rate of from about 0.25 inch per minute to about2 inches per minute provide a functional coating. However, valuesoutside of those set forth above can be acceptable or even desirable incertain embodiments, for example, dependent upon viscosity and surfacetension as is appreciated by one skilled in the art. In one embodiment,the enzyme domain 49 is formed by dip coating two times (namely, formingtwo layers) in a coating solution and curing at 50° C. under vacuum for20 minutes. However, in some embodiments, the enzyme domain can beformed by dip-coating and/or spray-coating one or more layers at apredetermined concentration of the coating solution, insertion rate,dwell time, withdrawal rate, and/or desired thickness.

Transcutaneous sensors of preferred embodiments preferably exhibit100±10% functionality, more preferably ˜100% functionality overphysiological glucose concentrations (from about 40 mg/dL to about 400mg/dL) at oxygen concentrations preferably as low as about 0.6 mg/L orless, more preferably about 0.3 mg/L or less, more preferably stillabout 0.25 mg/L or less, even more preferably about 0.15 mg/L or less,even more preferably still about 0.1 mg/L or less, and most preferablyabout 0.05 mg/L or less. The transcutaneous glucose sensors of preferredembodiments typically consume 1 μg or less of enzyme over theiroperational lifetimes (typically 7 days or less).

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain 50 disposed more distal from the electroactive surfaces than theenzyme domain 49. Although the following description is directed to aresistance domain for a glucose sensor, the resistance domain can bemodified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21 (1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, glucose linearityis lost at concentrations of glucose within a physiologically relevantrange. Without a semipermeable membrane situated over the enzyme domainto control the flux of glucose and oxygen, a linear response to glucoselevels can be obtained only for glucose concentrations that are lessthan physiologically relevant concentrations, i.e., less than 40 mg/dL.See, e.g., Luong, J H et al., Characterization of interactingferrocene-cyclosdextrin systems and their role in mediated bisensors, J.Mol. Recognit. 1995, Jan. 8 (1-2), 132-138. However, in a clinicalsetting, a linear response to glucose levels is desirable up to at leastabout 400 mg/dL. The sensors of preferred embodiments typically exhibitsubstantial linearity (e.g., r² of 0.95 or greater in vitro) atphysiologically relevant concentrations of from about 40 mg/dL or lessup to about 400 mg/dL glucose or more.

The resistance domain 50 includes a semi permeable membrane thatcontrols the flux of oxygen and glucose to the underlying enzyme domain49, preferably rendering oxygen in a non-rate-limiting excess. As aresult, the upper limit of linearity of glucose measurement is extendedto a much higher value than that which is achieved without theresistance domain. In one embodiment, the resistance domain 50 exhibitsan oxygen to glucose permeability ratio of from about 50:1 or less toabout 400:1 or more, preferably about 200:1. As a result,one-dimensional reactant diffusion is adequate to provide excess oxygenat all reasonable glucose and oxygen concentrations found in thesubcutaneous matrix (See Rhodes et al., Anal. Chem., 66:1520-1529(1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain49. If more oxygen is supplied to the enzyme, then more glucose can alsobe supplied to the enzyme without creating an oxygen rate-limitingexcess. In alternative embodiments, the resistance domain is formed froma silicone composition, such as is described in co-pending U.S. Pat.Publ. No. 2005-0090607 entitled, “SILICONE COMPOSITION FOR BIOCOMPATIBLEMEMBRANE.”

In a preferred embodiment, the resistance domain 50 includes apolyurethane membrane with both hydrophilic and hydrophobic regions tocontrol the diffusion of glucose and oxygen to an analyte sensor, themembrane being fabricated easily and reproducibly from commerciallyavailable materials. A suitable hydrophobic polymer component is apolyurethane, or polyetherurethaneurea. Polyurethane is a polymerproduced by the condensation reaction of a diisocyanate and adifunctional hydroxyl-containing material. A polyurethaneurea is apolymer produced by the condensation reaction of a diisocyanate and adifunctional amine-containing material. Preferred diisocyanates includealiphatic diisocyanates containing from about 4 to about 8 methyleneunits. Diisocyanates containing cycloaliphatic moieties can also beuseful in the preparation of the polymer and copolymer components of themembranes of preferred embodiments. The material that forms the basis ofthe hydrophobic matrix of the resistance domain can be any of thoseknown in the art as appropriate for use as membranes in sensor devicesand as having sufficient permeability to allow relevant compounds topass through it, for example, to allow an oxygen molecule to passthrough the membrane from the sample under examination in order to reachthe active enzyme or electrochemical electrodes. Examples of materialswhich can be used to make non-polyurethane type membranes include vinylpolymers, polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In preferred embodiments, the resistance domain 50 is deposited onto theenzyme domain 49 to yield a domain thickness of from about 0.05 micronor less to about 20 microns or more, more preferably from about 0.05,0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,or 19.5 microns, and more preferably from about 2, 2.5 or 3 microns toabout 3.5, 4, 4.5, or 5 microns. Preferably, the resistance domain isdeposited onto the enzyme domain by spray coating or dip coating. Incertain embodiments, spray coating is the preferred depositiontechnique. The spraying process atomizes and mists the solution, andtherefore most or all of the solvent is evaporated prior to the coatingmaterial settling on the underlying domain, thereby minimizing contactof the solvent with the enzyme. One additional advantage ofspray-coating the resistance domain as described in the preferredembodiments includes formation of a membrane system that substantiallyblocks or resists ascorbate (a known electrochemical interferant inhydrogen peroxide-measuring glucose sensors). While not wishing to bebound by theory, it is believed that during the process of depositingthe resistance domain as described in the preferred embodiments, astructural morphology is formed, characterized in that ascorbate doesnot substantially permeate there through.

In preferred embodiments, the resistance domain 50 is deposited on theenzyme domain 49 by spray-coating a solution of from about 1 wt. % toabout 5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent.In spraying a solution of resistance domain material, including asolvent, onto the enzyme domain, it is desirable to mitigate orsubstantially reduce any contact with enzyme of any solvent in the spraysolution that can deactivate the underlying enzyme of the enzyme domain49. Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Although a variety of spraying or deposition techniques can be used,spraying the resistance domain material and rotating the sensor at leastone time by 180° can provide adequate coverage by the resistance domain.Spraying the resistance domain material and rotating the sensor at leasttwo times by 120 degrees provides even greater coverage (one layer of360° coverage), thereby ensuring resistivity to glucose, such as isdescribed in more detail above.

In preferred embodiments, the resistance domain 50 is spray-coated andsubsequently cured for a time of from about 15 to about 90 minutes at atemperature of from about 40 to about 60° C. (and can be accomplishedunder vacuum (e.g., 20 to 30 mmHg)). A cure time of up to about 90minutes or more can be advantageous to ensure complete drying of theresistance domain. While not wishing to be bound by theory, it isbelieved that complete drying of the resistance domain aids instabilizing the sensitivity of the glucose sensor signal. It reducesdrifting of the signal sensitivity over time, and complete drying isbelieved to stabilize performance of the glucose sensor signal in loweroxygen environments.

In one embodiment, the resistance domain 50 is formed by spray-coatingat least six layers (namely, rotating the sensor seventeen times by 120°for at least six layers of 360° coverage) and curing at 50° C. undervacuum for 60 minutes. However, the resistance domain can be formed bydip-coating or spray-coating any layer or plurality of layers, dependingupon the concentration of the solution, insertion rate, dwell time,withdrawal rate, and/or the desired thickness of the resulting film.

Mutarotase Enzyme

In some embodiments, mutarotase, an enzyme that converts α D-glucose toβ D-glucose, is incorporated into the membrane system. Mutarotase can beincorporated into the enzyme domain and/or can be incorporated intoanother domain of the membrane system. In general, glucose exists in twodistinct isomers, α and β, which are in equilibrium with one another insolution and in the blood or interstitial fluid. At equilibrium, α ispresent at a relative concentration of about 35.5% and β is present inthe relative concentration of about 64.5% (see Okuda et. al., AnalBiochem. 1971 September; 43(1):312-5). Glucose oxidase, which is aconventional enzyme used to react with glucose in glucose sensors,reacts with β D-glucose and not with α D-glucose. Since only the βD-glucose isomer reacts with the glucose oxidase, errant readings mayoccur in a glucose sensor responsive to a shift of the equilibriumbetween the α D-glucose and the β D-glucose. Many compounds, such ascalcium, can affect equilibrium shifts of α D-glucose and β D-glucose.For example, as disclosed in U.S. Pat. No. 3,964,974 to Banaugh et al.,compounds that exert a mutarotation accelerating effect on α D-glucoseinclude histidine, aspartic acid, imidazole, glutamic acid, α hydroxylpyridine, and phosphate.

Accordingly, a shift in α D-glucose and β D-glucose equilibrium cancause a glucose sensor based on glucose oxidase to err high or low. Toovercome the risks associated with errantly high or low sensor readingsdue to equilibrium shifts, the sensor of the preferred embodiments canbe configured to measure total glucose in the host, including αD-glucose and β D-glucose by the incorporation of the mutarotase enzyme,which converts α D-glucose to β D-glucose.

Although sensors of some embodiments described herein include anoptional interference domain in order to block or reduce one or moreinterferants, sensors with the membrane system of the preferredembodiments, including an electrode domain 47, an enzyme domain 48, anda resistance domain 49, has been shown to inhibit ascorbate without anadditional interference domain. Namely, the membrane system of thepreferred embodiments, including an electrode domain 47, an enzymedomain 48, and a resistance domain 49, has been shown to besubstantially non-responsive to ascorbate in physiologically acceptableranges. While not wishing to be bound by theory, it is believed that theprocessing process of spraying the depositing the resistance domain byspray coating, as described herein, forms results in a structuralmorphology that is substantially resistance resistant to ascorbate.

Interference-Free Membrane Systems

In general, it is believed that appropriate solvents and/or depositionmethods can be chosen for one or more of the domains of the membranesystem that form one or more transitional domains such that interferantsdo not substantially permeate there through. Thus, sensors can be builtwithout distinct or deposited interference domains, which arenon-responsive to interferants. While not wishing to be bound by theory,it is believed that a simplified multilayer membrane system, more robustmultilayer manufacturing process, and reduced variability caused by thethickness and associated oxygen and glucose sensitivity of the depositedmicron-thin interference domain can be provided. Additionally, theoptional polymer-based interference domain, which usually inhibitshydrogen peroxide diffusion, is eliminated, thereby enhancing the amountof hydrogen peroxide that passes through the membrane system.

Oxygen Conduit

As described above, certain sensors depend upon an enzyme within themembrane system through which the host's bodily fluid passes and inwhich the analyte (for example, glucose) within the bodily fluid reactsin the presence of a co-reactant (for example, oxygen) to generate aproduct. The product is then measured using electrochemical methods, andthus the output of an electrode system functions as a measure of theanalyte. For example, when the sensor is a glucose oxidase based glucosesensor, the species measured at the working electrode is H₂O₂. Anenzyme, glucose oxidase, catalyzes the conversion of oxygen and glucoseto hydrogen peroxide and gluconate according to the following reaction:Glucose+O₂→Gluconate+H₂O₂

Because for each glucose molecule reacted there is a proportional changein the product, H₂O₂, one can monitor the change in H₂O₂ to determineglucose concentration. Oxidation of H₂O₂ by the working electrode isbalanced by reduction of ambient oxygen, enzyme generated H₂O₂ and otherreducible species at a counter electrode, for example. See Fraser, D.M., “An Introduction to In vivo Biosensing: Progress and Problems.” In“Biosensors and the Body,” D. M. Fraser, ed., 1997, pp. 1-56 John Wileyand Sons, New York))

In vivo, glucose concentration is generally about one hundred times ormore that of the oxygen concentration. Consequently, oxygen is alimiting reactant in the electrochemical reaction, and when insufficientoxygen is provided to the sensor, the sensor is unable to accuratelymeasure glucose concentration. Thus, depressed sensor function orinaccuracy is believed to be a result of problems in availability ofoxygen to the enzyme and/or electroactive surface(s).

Accordingly, in an alternative embodiment, an oxygen conduit (forexample, a high oxygen solubility domain formed from silicone orfluorochemicals) is provided that extends from the ex vivo portion ofthe sensor to the in vivo portion of the sensor to increase oxygenavailability to the enzyme. The oxygen conduit can be formed as a partof the coating (insulating) material or can be a separate conduitassociated with the assembly of wires that forms the sensor.

Porous Biointerface Materials

In alternative embodiments, the distal portion 42 includes a porousmaterial disposed over some portion thereof, which modifies the host'stissue response to the sensor. In some embodiments, the porous materialsurrounding the sensor advantageously enhances and extends sensorperformance and lifetime in the short term by slowing or reducingcellular migration to the sensor and associated degradation that wouldotherwise be caused by cellular invasion if the sensor were directlyexposed to the in vivo environment. Alternatively, the porous materialcan provide stabilization of the sensor via tissue ingrowth into theporous material in the long term. Suitable porous materials includesilicone, polytetrafluoroethylene, expanded polytetrafluoroethylene,polyethylene-co-tetrafluoro ethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinylalcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate(PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes,cellulosic polymers, polysulfones and block copolymers thereofincluding, for example, di-block, tri-block, alternating, random andgraft copolymers, as well as metals, ceramics, cellulose, hydrogelpolymers, poly (2-hydroxyethyl methacrylate, pHEMA), hydroxyethylmethacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC),high density polyethylene, acrylic copolymers, nylon, polyvinyldifluoride, polyanhydrides, poly(l-lysine), poly (L-lactic acid),hydroxyethylmethacrylate, hydroxyapeptite, alumina, zirconia, carbonfiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol,stainless steel, and CoCr alloy, or the like, such as are described inco-pending U.S. patent application Ser. No. 10/842,716, filed May 10,2004 and entitled, “BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVEAGENTS” and U.S. patent application Ser. No. 10/647,065 filed Aug. 22,2003 and entitled “POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES.”

In some embodiments, the porous material surrounding the sensor providesunique advantages in the short term (e.g., one to 14 days) that can beused to enhance and extend sensor performance and lifetime. However,such materials can also provide advantages in the long term too (e.g.,greater than 14 days). Particularly, the in vivo portion of the sensor(the portion of the sensor that is implanted into the host's tissue) isencased (partially or fully) in a porous material. The porous materialcan be wrapped around the sensor (for example, by wrapping the porousmaterial around the sensor or by inserting the sensor into a section ofporous material sized to receive the sensor). Alternately, the porousmaterial can be deposited on the sensor (for example, by electrospinningof a polymer directly thereon). In yet other alternative embodiments,the sensor is inserted into a selected section of porous biomaterial.Other methods for surrounding the in vivo portion of the sensor with aporous material can also be used as is appreciated by one skilled in theart.

The porous material surrounding the sensor advantageously slows orreduces cellular migration to the sensor and associated degradation thatwould otherwise be caused by cellular invasion if the sensor weredirectly exposed to the in vivo environment. Namely, the porous materialprovides a barrier that makes the migration of cells towards the sensormore tortuous and therefore slower (providing short term advantages). Itis believed that this reduces or slows the sensitivity loss normallyobserved in a short-term sensor over time.

In an embodiment wherein the porous material is a high oxygen solubilitymaterial, such as porous silicone, the high oxygen solubility porousmaterial surrounds some of or the entire in vivo portion 42 of thesensor. High oxygen solubility materials are materials that dynamicallyretain a high availability of oxygen that can be used to compensate forthe local oxygen deficit during times of transient ischemia (e.g.,silicone and fluorocarbons). It is believed that some signal noisenormally seen by a conventional sensor can be attributed to an oxygendeficit. In one exemplary embodiment, porous silicone surrounds thesensor and thereby effectively increases the concentration of oxygenlocal (proximal) to the sensor. Thus, an increase in oxygen availabilityproximal to the sensor as achieved by this embodiment ensures that anexcess of oxygen over glucose is provided to the sensor; therebyreducing the likelihood of oxygen limited reactions therein.Accordingly, by providing a high oxygen solubility material (e.g.,porous silicone) surrounding the in vivo portion of the sensor, it isbelieved that increased oxygen availability, reduced signal noise,longevity, and ultimately enhanced sensor performance can be achieved.

Bioactive Agents

In some alternative embodiments, a bioactive agent is incorporated intothe above described porous material and/or membrane system, such as isdescribed in co-pending U.S. patent application Ser. No. 10/842,716,which diffuses out into the environment adjacent to the sensing region.Additionally or alternately, a bioactive agent can be administeredlocally at the exit-site or implantation-site. Suitable bioactive agentsare those that modify the host's tissue response to the sensor, forexample anti-inflammatory agents, anti-infective agents, anesthetics,inflammatory agents, growth factors, immunosuppressive agents,antiplatelet agents, anti-coagulants, anti-proliferates, ACE inhibitors,cytotoxic agents, anti-barrier cell compounds, vascularization-inducingcompounds, anti-sense molecules, or mixtures thereof, such as aredescribed in more detail in co-pending U.S. patent application Ser. No.10/842,716.

In embodiments wherein the porous material is designed to enhanceshort-term (e.g., between about 1 and 14 days) lifetime or performanceof the sensor, a suitable bioactive agent can be chosen to ensure thattissue ingrowth does not substantially occur within the pores of theporous material. Namely, by providing a tissue modifying bioactiveagent, such as an anti-inflammatory agent (for example, Dexamethasone),substantially tissue ingrowth can be inhibited, at least in the shortterm, in order to maintain sufficient glucose transport through thepores of the porous material to maintain a stable sensitivity.

In embodiments wherein the porous material is designed to enhancelong-term (e.g., between about a day to a year or more) lifetime orperformance of the sensor, a suitable bioactive agent, such as avascularization-inducing compound or anti-barrier cell compound, can bechosen to encourage tissue ingrowth without barrier cell formation.

In some alternative embodiments, the in vivo portion of the sensor isdesigned with porosity there through, for example, a design wherein thesensor wires are configured in a mesh, loose helix configuration(namely, with spaces between the wires), or with micro-fabricated holesthere through. Porosity within the sensor modifies the host's tissueresponse to the sensor, because tissue ingrowth into and/or through thein vivo portion of the sensor increases stability of the sensor and/orimproves host acceptance of the sensor, thereby extending the lifetimeof the sensor in vivo.

In some alternative embodiments, the sensor is manufactured partially orwholly using a continuous reel-to-reel process, wherein one or moremanufacturing steps are automated. In such embodiments, a manufacturingprocess can be provided substantially without the need for manualmounting and fixturing steps and substantially without the need humaninteraction. A process can be utilized wherein a plurality of sensors ofthe preferred embodiments, including the electrodes, insulator, andmembrane system, are continuously manufactured in a semi-automated orautomated process.

In one embodiment, a plurality of twisted pairs are continuously formedinto a coil, wherein a working electrode is coated with an insulatormaterial around which a plurality of reference electrodes are wound. Theplurality of twisted pairs are preferably indexed and subsequently movedfrom one station to the next whereby the membrane system is seriallydeposited according to the preferred embodiments. Preferably, the coilis continuous and remains as such during the entire sensor fabricationprocess, including winding of the electrodes, insulator application, andmembrane coating processes. After drying of the membrane system, eachindividual sensor is cut from the continuous coil.

A continuous reel-to-reel process for manufacturing the sensoreliminates possible sensor damage due to handling by eliminatinghandling steps, and provides faster manufacturing due to faster troubleshooting by isolation when a product fails. Additionally, a process runcan be facilitated because of elimination of steps that would otherwisebe required (e.g., steps in a manual manufacturing process). Finally,increased or improved product consistency due to consistent processeswithin a controlled environment can be achieved in a machine or robotdriven operation.

In one alternative embodiment, a continuous manufacturing process iscontemplated that utilizes physical vapor deposition in a vacuum to formthe sensor. Physical vapor deposition can be used to coat one or moreinsulating layers onto the electrodes, and further can be used todeposit the membrane system thereon. While not wishing to be bound bytheory, it is believed that by implementing physical vapor deposition toform some portions or the entire sensor of the preferred embodiments,simplified manufacturing, consistent deposition, and overall increasedreproducibility can be achieved.

Measurement of PicoAmp Signals

Advantageously, sensors with the membrane system of the preferredembodiments, including an electrode domain 47 and/or interference domain48, an enzyme domain 49, and a resistance domain 50, provide stablesignal response to increasing glucose levels of from about 40 to about400 mg/dL, and sustained function (at least 90% signal strength) even atlow oxygen levels (for example, at about 0.6 mg/L O₂). While not wishingto be bound by theory, it is believed that the resistance domainprovides sufficient resistivity, or the enzyme domain providessufficient enzyme, such that oxygen limitations are seen at a much lowerconcentration of oxygen as compared to prior art sensors.

In preferred embodiments, a sensor signal with a current in the picoAmprange is preferred, which is described in more detail elsewhere herein.However, the ability to produce a signal with a current in the picoAmprange can be dependent upon a combination of factors, including theelectronic circuitry design (e.g., A/D converter, bit resolution, andthe like), the membrane system (e.g., permeability of the analytethrough the resistance domain, enzyme concentration, and/or electrolyteavailability to the electrochemical reaction at the electrodes), and theexposed surface area of the working electrode. For example, theresistance domain can be designed to be more or less restrictive to theanalyte depending upon to the design of the electronic circuitry,membrane system, and/or exposed electroactive surface area of theworking electrode.

Accordingly, in preferred embodiments, the membrane system is designedwith a sensitivity of from about 1 pA/mg/dL to about 100 pA/mg/dL,preferably from about 5 pA/mg/dL to about 25 pA/mg/dL, and morepreferably from about 4 pA/mg/dL to about 7 pA/mg/dL. While not wishingto be bound by any particular theory, it is believed that membranesystems designed with a sensitivity in the preferred ranges permitmeasurement of the analyte signal in low analyte and/or low oxygensituations. Namely, conventional analyte sensors have shown reducedmeasurement accuracy in low analyte ranges due to lower availability ofthe analyte to the sensor and/or have shown increased signal noise inhigh analyte ranges due to insufficient oxygen necessary to react withthe amount of analyte being measured. While not wishing to be bound bytheory, it is believed that the membrane systems of the preferredembodiments, in combination with the electronic circuitry design andexposed electrochemical reactive surface area design, supportmeasurement of the analyte in the picoAmp range, which enables animproved level of resolution and accuracy in both low and high analyteranges not seen in the prior art.

Applicator

FIG. 6 is an exploded side view of an applicator, showing the componentsthat enable sensor and needle insertion. In this embodiment, theapplicator 12 includes an applicator body 18 that aides in aligning andguiding the applicator components. Preferably, the applicator body 18includes an applicator body base 60 that matingly engages the mountingunit 14 and an applicator body cap 62 that enables appropriaterelationships (for example, stops) between the applicator components.

The guide tube subassembly 20 includes a guide tube carrier 64 and aguide tube 66. In some embodiments, the guide tube is a cannula. Theguide tube carrier 64 slides along the applicator body 18 and maintainsthe appropriate relative position of the guide tube 66 during insertionand subsequent retraction. For example, prior to and during insertion ofthe sensor, the guide tube 66 extends through the contact subassembly 26to maintain an opening that enables easy insertion of the needle therethrough (see FIGS. 7A to 7D). During retraction of the sensor, the guidetube subassembly 20 is pulled back, engaging with and causing the needleand associated moving components to retract back into the applicator 12(See FIGS. 7C and 7D).

A needle subassembly 68 is provided that includes a needle carrier 70and needle 72. The needle carrier 70 cooperates with the otherapplicator components and carries the needle 72 between its extended andretracted positions. The needle can be of any appropriate size that canencompass the sensor 32 and aid in its insertion into the host.Preferred sizes include from about 32 gauge or less to about 18 gauge ormore, more preferably from about 28 gauge to about 25 gauge, to providea comfortable insertion for the host. Referring to the inner diameter ofthe needle, approximately 0.006 inches to approximately 0.023 inches ispreferable, and 0.013 inches is most preferable. The needle carrier 70is configured to engage with the guide tube carrier 64, while the needle72 is configured to slidably nest within the guide tube 66, which allowsfor easy guided insertion (and retraction) of the needle through thecontact subassembly 26.

A push rod subassembly 74 is provided that includes a push rod carrier76 and a push rod 78. The push rod carrier 76 cooperates with otherapplicator components to ensure that the sensor is properly insertedinto the host's skin, namely the push rod carrier 76 carries the pushrod 78 between its extended and retracted positions. In this embodiment,the push rod 78 is configured to slidably nest within the needle 72,which allows for the sensor 32 to be pushed (released) from the needle72 upon retraction of the needle, which is described in more detail withreference to FIGS. 7A through 7D. In some embodiments, a slight bend orserpentine shape is designed into or allowed in the sensor in order tomaintain the sensor within the needle by interference. While not wishingto be bound by theory, it is believed that a slight friction fit of thesensor within the needle minimizes motion of the sensor duringwithdrawal of the needle and maintains the sensor within the needleprior to withdrawal of the needle.

A plunger subassembly 22 is provided that includes a plunger 80 andplunger cap 82. The plunger subassembly 22 cooperates with otherapplicators components to ensure proper insertion and subsequentretraction of the applicator components. In this embodiment, the plunger80 is configured to engage with the push rod to ensure the sensorremains extended (namely, in the host) during retraction, such as isdescribed in more detail with reference to FIG. 7C.

Sensor Insertion

FIGS. 7A through 7D are schematic side cross-sectional views thatillustrate the applicator components and their cooperating relationshipsat various stages of sensor insertion. FIG. 7A illustrates the needleand sensor loaded prior to sensor insertion. FIG. 7B illustrates theneedle and sensor after sensor insertion. FIG. 7C illustrates the sensorand needle during needle retraction. FIG. 7D illustrates the sensorremaining within the contact subassembly after needle retraction.Although the embodiments described herein suggest manual insertionand/or retraction of the various components, automation of one or moreof the stages can also be employed. For example, spring-loadedmechanisms that can be triggered to automatically insert and/or retractthe sensor, needle, or other cooperative applicator components can beimplemented.

Referring to FIG. 7A, the sensor 32 is shown disposed within the needle72, which is disposed within the guide tube 66. In this embodiment, theguide tube 66 is provided to maintain an opening within the contactsubassembly 26 and/or contacts 28 to provide minimal friction betweenthe needle 72 and the contact subassembly 26 and/or contacts 28 duringinsertion and retraction of the needle 72. However, the guide tube is anoptional component, which can be advantageous in some embodimentswherein the contact subassembly 26 and/or the contacts 28 are formedfrom an elastomer or other material with a relatively high frictioncoefficient, and which can be omitted in other embodiments wherein thecontact subassembly 26 and or the contacts 28 are formed from a materialwith a relatively low friction coefficient (for example, hard plastic ormetal). A guide tube, or the like, can be preferred in embodimentswherein the contact subassembly 26 and/or the contacts 28 are formedfrom a material designed to frictionally hold the sensor 32 (see FIG.7D), for example, by the relaxing characteristics of an elastomer, orthe like. In these embodiments, the guide tube is provided to easeinsertion of the needle through the contacts, while allowing for africtional hold of the contacts on the sensor 32 upon subsequent needleretraction. Stabilization of the sensor in or on the contacts 28 isdescribed in more detail with reference to FIG. 7D and following.Although FIG. 7A illustrates the needle and sensor inserted into thecontacts subassembly as the initial loaded configuration, alternativeembodiments contemplate a step of loading the needle through the guidetube 66 and/or contacts 28 prior to sensor insertion.

Referring to FIG. 7B, the sensor 32 and needle 72 are shown in anextended position. In this stage, the pushrod 78 has been forced to aforward position, for example by pushing on the plunger shown in FIG. 6,or the like. The plunger 22 (FIG. 6) is designed to cooperate with otherof the applicator components to ensure that sensor 32 and the needle 72extend together to a forward position (as shown); namely, the push rod78 is designed to cooperate with other of the applicator components toensure that the sensor 32 maintains the forward position simultaneouslywithin the needle 72.

Referring to FIG. 7C, the needle 72 is shown during the retractionprocess. In this stage, the push rod 78 is held in its extended(forward) position in order to maintain the sensor 32 in its extended(forward) position until the needle 72 has substantially fully retractedfrom the contacts 28. Simultaneously, the cooperating applicatorcomponents retract the needle 72 and guide tube 66 backward by a pullingmotion (manual or automated) thereon. In preferred embodiments, theguide tube carrier 64 (FIG. 6) engages with cooperating applicatorcomponents such that a backward (retraction) motion applied to the guidetube carrier retracts the needle 72 and guide tube 66, without(initially) retracting the push rod 78. In an alternative embodiment,the push rod 78 can be omitted and the sensor 32 held it its forwardposition by a cam, elastomer, or the like, which is in contact with aportion of the sensor while the needle moves over another portion of thesensor. One or more slots can be cut in the needle to maintain contactwith the sensor during needle retraction.

Referring to FIG. 7D, the needle 72, guide tube 66, and push rod 78 areall retracted from contact subassembly 26, leaving the sensor 32disposed therein. The cooperating applicator components are designedsuch that when the needle 72 has substantially cleared from the contacts28 and/or contact subassembly 26, the push rod 78 is retracted alongwith the needle 72 and guide tube 66. The applicator 12 can then bereleased (manually or automatically) from the contacts 28, such as isdescribed in more detail elsewhere herein, for example with reference toFIGS. 8C and 9A.

The preferred embodiments are generally designed with elastomericcontacts to ensure a retention force that retains the sensor 32 withinthe mounting unit 14 and to ensure stable electrical connection of thesensor 32 and its associated contacts 28. Although the illustratedembodiments and associated text describe the sensor 32 extending throughthe contacts 28 to form a friction fit therein, a variety ofalternatives are contemplated. In one alternative embodiment, the sensoris configured to be disposed adjacent to the contacts (rather thanbetween the contacts). The contacts can be constructed in a variety ofknown configurations, for example, metallic contacts, cantileveredfingers, pogo pins, or the like, which are configured to press againstthe sensor after needle retraction.

The illustrated embodiments are designed with coaxial contacts 28;namely, the contacts 28 are configured to contact the working andreference electrodes 44, 46 axially along the distal portion 42 of thesensor 32 (see FIG. 5A). As shown in FIG. 5A, the working electrode 44extends farther than the reference electrode 46, which allows coaxialconnection of the electrodes 44, 46 with the contacts 28 at locationsspaced along the distal portion of the sensor (see also FIGS. 9B and10B). Although the illustrated embodiments employ a coaxial design,other designs are contemplated within the scope of the preferredembodiments. For example, the reference electrode can be positionedsubstantially adjacent to (but spaced apart from) the working electrodeat the distal portion of the sensor. In this way, the contacts 28 can bedesigned side-by-side rather than coaxially along the axis of thesensor.

FIGS. 8A to 8C are side views of an applicator and mounting, showingvarious stages of sensor insertion. FIG. 8A is a side view of theapplicator matingly engaged to the mounting unit prior to sensorinsertion. FIG. 8B is a side view of the mounting unit and applicatorafter the plunger subassembly has been pushed, extending the needle andsensor from the mounting unit (namely, through the host's skin). FIG. 8Cis a side view of the mounting unit and applicator after the guide tubesubassembly has been retracted, retracting the needle back into theapplicator. Although the drawings and associated text illustrate anddescribe embodiments wherein the applicator is designed for manualinsertion and/or retraction, automated insertion and/or retraction ofthe sensor/needle, for example, using spring-loaded components, canalternatively be employed.

The preferred embodiments advantageously provide a system and method foreasy insertion of the sensor and subsequent retraction of the needle ina single push-pull motion. Because of the mechanical latching system ofthe applicator, the user provides a continuous force on the plunger cap82 and guide tube carrier 64 that inserts and retracts the needle in acontinuous motion. When a user grips the applicator, his or her fingersgrasp the guide tube carrier 64 while his or her thumb (or anotherfinger) is positioned on the plunger cap 82. The user squeezes his orher fingers and thumb together continuously, which causes the needle toinsert (as the plunger slides forward) and subsequently retract (as theguide tube carrier slides backward) due to the system of latches locatedwithin the applicator (FIGS. 6 to 8) without any necessary change ofgrip or force, leaving the sensor implanted in the host. In someembodiments, a continuous torque, when the applicator components areconfigured to rotatingly engage one another, can replace the continuousforce. Some prior art sensors, in contrast to the sensors of thepreferred embodiments, suffer from complex, multi-step, ormulti-component insertion and retraction steps to insert and remove theneedle from the sensor system.

FIG. 8A shows the mounting unit and applicator in the ready position.The sensor system can be shipped in this configuration, or the user canbe instructed to mate the applicator 12 with the mounting unit 14 priorto sensor insertion. The insertion angle α is preferably fixed by themating engagement of the applicator 12. In the illustrated embodiment,the insertion angle α is fixed in the applicator 12 by the angle of theapplicator body base 60 with the shaft of the applicator body 18.However, a variety of systems and methods of ensuring proper placementcan be implemented. Proper placement ensures that at least a portion ofthe sensor 32 extends below the dermis of the host upon insertion. Inalternative embodiments, the sensor system 10 is designed with a varietyof adjustable insertion angles. A variety of insertion angles can beadvantageous to accommodate a variety of insertion locations and/orindividual dermis configurations (for example, thickness of the dermis).In preferred embodiments, the insertion angle α is from about 0 to about90 degrees, more preferably from about 30 to about 60 degrees, and evenmore preferably about 45 degrees.

Mounting Unit

In practice, the mounting unit is placed at an appropriate location onthe host's skin, for example, the skin of the arm, thigh, or abdomen.Thus, removing the backing layer 9 from the adhesive pad 8 and pressingthe base portion of the mounting unit on the skin adheres the mountingunit to the host's skin.

FIG. 8B shows the mounting unit and applicator after the needle 72 hasbeen extended from the mounting unit 14 (namely, inserted into the host)by pushing the push rod subassembly 22 into the applicator 12. In thisposition, the sensor 32 is disposed within the needle 72 (namely, inposition within the host), and held by the cooperating applicatorcomponents. In alternative embodiments, the mounting unit and/orapplicator can be configured with the needle/sensor initially extended.In this way, the mechanical design can be simplified and theplunger-assisted insertion step can be eliminated or modified. Theneedle can be simply inserted by a manual force to puncture the host'sskin, and only one (pulling) step is required on the applicator, whichremoves the needle from the host's skin.

FIG. 8C shows the mounting unit and applicator after the needle 72 hasbeen retracted into the applicator 12, exposing the sensor 32 to thehost's tissue. During needle retraction, the push rod subassemblymaintains the sensor in its extended position (namely, within the host).In preferred embodiments, retraction of the needle irreversibly locksthe needle within the applicator so that it cannot be accidentallyand/or intentionally released, reinserted, or reused. The applicator ispreferably configured as a disposable device to reduce or eliminate apossibility of exposure of the needle after insertion into the host.However a reusable or reloadable applicator is also contemplated in somealternative embodiments. After needle retraction, the applicator 12 canbe released from the mounting unit, for example, by pressing the releaselatch(es) 30, and the applicator disposed of appropriately. Inalternative embodiments, other mating and release configurations can beimplemented between the mounting unit and the applicator, or theapplicator can automatically release from the mounting unit after sensorinsertion and subsequent needle retraction. In one alternativeembodiment, a retention hold (e.g., ball and detent configuration) holdsand releases the electronics unit (or applicator).

In one alternative embodiment, the mounting unit is configured toreleasably mate with the applicator and electronics unit, such that whenthe applicator is releasably mated to the mounting unit (e.g., aftersensor insertion), the electronics unit is configured to slide into themounting unit, thereby triggering release of the applicator andsimultaneous mating of the electronics unit to the mounting unit.Cooperating mechanical components, for example, sliding ball and detenttype configurations, can be used to accomplish the simultaneous matingof electronics unit and release of the applicator.

In some embodiments, the sensor 32 exits the base of the mounting unit14 at a location distant from an edge of the base. In some embodiments,the sensor 32 exits the base of the mounting unit 14 at a locationsubstantially closer to the center than the edges thereof. While notwishing to be bound by theory, it is believed that by providing an exitport for the sensor 32 located away from the edges, the sensor 32 can beprotected from motion between the body and the mounting unit, snaggingof the sensor by an external source, and/or environmental contaminantsthat can migrate under the edges of the mounting unit. In someembodiments, the sensor exits the mounting unit away from an outer edgeof the device. In some alternative embodiments, however, the sensorexits the mounting unit 14 at an edge or near an edge of the device. Insome embodiments, the mounting unit is configured such that the exitport (location) of the sensor is adjustable; thus, in embodimentswherein the depth of the sensor insertion is adjustable, six-degrees offreedom can thereby be provided.

Extensible Adhesive Pad

In certain embodiments, an adhesive pad is used with the sensor system.A variety of design parameters are desirable when choosing an adhesivepad for the mounting unit. For example: 1) the adhesive pad can bestrong enough to maintain full contact at all times and during allmovements (devices that release even slightly from the skin have agreater risk of contamination and infection), 2) the adhesive pad can bewaterproof or water permeable such that the host can wear the deviceeven while heavily perspiring, showering, or even swimming in somecases, 3) the adhesive pad can be flexible enough to withstand linearand rotational forces due to host movements, 4) the adhesive pad can becomfortable for the host, 5) the adhesive pad can be easily releasableto minimize host pain, 6) and/or the adhesive pad can be easilyreleasable so as to protect the sensor during release. Unfortunately,these design parameters are difficult to simultaneously satisfy usingknown adhesive pads, for example, strong medical adhesive pads areavailable but are usually non-precise (for example, requiringsignificant “ripping” force during release) and can be painful duringrelease due to the strength of their adhesion.

Therefore, the preferred embodiments provide an adhesive pad 8′ formounting the mounting unit onto the host, including a sufficientlystrong medical adhesive pad that satisfies one or more strength andflexibility requirements described above, and further provides a foreasy, precise and pain-free release from the host's skin. FIG. 9A is aside view of the sensor assembly, illustrating the sensor implanted intothe host with mounting unit adhered to the host's skin via an adhesivepad in one embodiment. Namely, the adhesive pad 8′ is formed from anextensible material that can be removed easily from the host's skin bystretching it lengthwise in a direction substantially parallel to (or upto about 35 degrees from) the plane of the skin. It is believed thatthis easy, precise, and painless removal is a function of both the highextensibility and easy stretchability of the adhesive pad.

In one embodiment, the extensible adhesive pad includes a polymeric foamlayer or is formed from adhesive pad foam. It is believed that theconformability and resiliency of foam aids in conformation to the skinand flexibility during movement of the skin. In another embodiment, astretchable solid adhesive pad, such as a rubber-based or anacrylate-based solid adhesive pad can be used. In another embodiment,the adhesive pad comprises a film, which can aid in increasing loadbearing strength and rupture strength of the adhesive pad

FIGS. 9B to 9C illustrate initial and continued release of the mountingunit from the host's skin by stretching the extensible adhesive pad inone embodiment. To release the device, the backing adhesive pad ispulled in a direction substantially parallel to (or up to about 35degrees from) the plane of the device. Simultaneously, the extensibleadhesive pad stretches and releases from the skin in a relatively easyand painless manner.

In one implementation, the mounting unit is bonded to the host's skinvia a single layer of extensible adhesive pad 8′, which is illustratedin FIGS. 9A to 9C. The extensible adhesive pad includes a substantiallynon-extensible pull-tab 52, which can include a light adhesive pad layerthat allows it to be held on the mounting unit 14 prior to release.Additionally, the adhesive pad can further include a substantiallynon-extensible holding tab 54, which remains attached to the mountingunit during release stretching to discourage complete and/oruncontrolled release of the mounting unit from the skin.

In one alternative implementation, the adhesive pad 8′ includestwo-sides, including the extensible adhesive pad and a backing adhesivepad (not shown). In this embodiment, the backing adhesive pad is bondedto the mounting unit's back surface 25 while the extensible adhesive pad8′ is bonded to the host's skin. Both adhesive pads provide sufficientstrength, flexibility, and waterproof or water permeable characteristicsappropriate for their respective surface adhesion. In some embodiments,the backing and extensible adhesive pads are particularly designed withan optimized bond for their respective bonding surfaces (namely, themounting unit and the skin).

In another alternative implementation, the adhesive pad 8′ includes adouble-sided extensible adhesive pad surrounding a middle layer orbacking layer (not shown). The backing layer can comprise a conventionalbacking film or can be formed from foam to enhance comfort,conformability, and flexibility. Preferably, each side of thedouble-sided adhesive pad is respectively designed for appropriatebonding surface (namely, the mounting unit and skin). A variety ofalternative stretch-release configurations are possible. Controlledrelease of one or both sides of the adhesive pad can be facilitated bythe relative lengths of each adhesive pad side, by incorporation of anon-adhesive pad zone, or the like.

Contact Subassembly

FIGS. 10A and 10B are perspective and side cross-sectional views,respectively, of the mounting unit immediately following sensorinsertion and release of the applicator from the mounting unit. In oneembodiment, such as illustrated in FIGS. 10A and 10B, the contactsubassembly 26 is held in its insertion position, substantially at theinsertion angle α of the sensor. Maintaining the contact subassembly 26at the insertion angle α during insertion enables the sensor 32 to beeasily inserted straight through the contact subassembly 26. The contactsubassembly 26 further includes a hinge 38 that allows movement of thecontact subassembly 26 from an angled to a flat position. The term“hinge,” as used herein, is a broad term and is used in its ordinarysense, including, without limitation, a mechanism that allowsarticulation of two or more parts or portions of a device. The term isbroad enough to include a sliding hinge, for example, a ball and detenttype hinging mechanism.

Although the illustrated embodiments describe a fixed insertion angledesigned into the applicator, alternative embodiments can design theinsertion angle into other components of the system. For example, theinsertion angle can be designed into the attachment of the applicatorwith the mounting unit, or the like. In some alternative embodiments, avariety of adjustable insertion angles can be designed into the systemto provide for a variety of host dermis configurations.

FIG. 10B illustrates the sensor 32 extending from the mounting unit 14by a preselected distance, which defines the depth of insertion of thesensor into the host. The dermal and subcutaneous make-up of animals andhumans is variable and a fixed depth of insertion may not be appropriatefor all implantations. Accordingly, in an alternative embodiment, thedistance that the sensor extends from the mounting unit is adjustable toaccommodate a variety of host body-types. For example, the applicator 12can be designed with a variety of adjustable settings, which control thedistance that the needle 72 (and therefore the sensor 32) extends uponsensor insertion. One skilled in the art appreciates a variety of meansand mechanisms can be employed to accommodate adjustable sensorinsertion depths, which are considered within the scope of the preferredembodiments. The preferred insertion depth is from about 0.1 mm or lessto about 2 cm or more, preferably from about 0.15, 0.2, 0.25, 0.3, 0.35,0.4, or 0.45 mm to about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, or 1.9 cm.

FIGS. 11A and 11B are perspective and side cross-sectional views,respectively, of the mounting unit after articulating the contactsubassembly to its functional position (which is also referred to as aninserted, implanted, or sensing position). The hinge 38 enables thecontact subassembly 26 to tilt from its insertion position (FIG. 10) toits functional position (FIG. 11) by pressing downward on the contactsubassembly, for example. Certain embodiments provide this pivotalmovement via two separate pieces (the contact subassembly 26 and themounting unit 14 connected by a hinge, for example, a mechanical oradhesive pad joint or hinge. A variety of pivoting, articulating, and/orhinging mechanisms can be employed with the sensors of preferredembodiments. For example, the hinge can be formed as a part of thecontact subassembly 26. The contact subassembly can be formed from aflexible piece of material (such as silicone, urethane rubber, or otherflexible or elastomeric material), wherein the material is sufficientlyflexible to enable bending or hinging of the contact subassembly from anangle appropriate for insertion (FIGS. 10A and 10B) to a lowerfunctional configuration (FIGS. 11A and 11B).

The relative pivotal movement of the contact subassembly isadvantageous, for example, for enabling the design of a low profiledevice while providing support for an appropriate needle insertionangle. In its insertion position, the sensor system is designed for easysensor insertion while forming a stable electrical connection with theassociated contacts 28. In its functional position, the sensor systemmaintains a low profile for convenience, comfort, and discreetnessduring use. Thus, the sensor systems of preferred embodiments areadvantageously designed with a hinging configuration to provide anoptimum guided insertion angle while maintaining a low profile deviceduring sensor use.

Sensor Members

In some embodiments, a shock-absorbing member or feature is incorporatedinto the design of the sensor and configured to absorb movement of thein vivo and/or ex vivo portion of the sensor. Conventional analytesensors can suffer from motion-related artifact associated with hostmovement when the host is using the device. For example, when atranscutaneous analyte sensor is inserted into the host, variousmovements on the sensor (for example, relative movement between the invivo portion and the ex vivo portion and/or movement within the host)create stresses on the device and can produce noise in the sensorsignal. Accordingly in some embodiments, a shock-absorbing member islocated on the sensor/mounting unit in a location that absorbs stressesassociated with the above-described movement.

In the preferred embodiments, the sensor 32 bends from a substantiallystraight to substantially bent configuration upon pivoting of thecontact subassembly from the insertion to functional position. Thesubstantially straight sensor configuration during insertionadvantageously provides ease of sensor insertion, while the substantialbend in the sensor in its functional position advantageously providesstability on the proximal end of the sensor with flexibility/mobility onthe distal end of the sensor. Additionally, motion within the mountingunit (e.g., caused by external forces to the mounting unit, movement ofthe skin, and the like) does not substantially translate to the in vivoportion of the sensor. Namely, the bend formed within the sensor 32functions to break column strength, causing flexion that effectivelyabsorbs movements on the sensor during use. Additionally, the sensor canbe designed with a length such that when the contact subassembly 26 ispivoted to its functional position (FIG. 10B), the sensor pushes forwardand flexes, allowing it to absorb motion between the in vivo and ex vivoportions of the sensor. It is believed that both of the above advantagesminimize motion artifact on the sensor signal and/or minimize damage tothe sensor caused by movement, both of which (motion artifact anddamage) have been observed in conventional transcutaneous sensors.

In some alternative embodiments, the shock-absorbing member can be anexpanding and contracting member, such as a spring, accordion,telescoping, or bellows-type device. In general, the shock absorbingmember can be located such that relative movement between the sensor,the mounting unit, and the host is absorbed without (or minimally)affecting the connection of the sensor to the mounting unit and/or thesensor stability within the implantation site; for example, theshock-absorbing member can be formed as a part of or connected to thesensor 32.

FIGS. 12A to 12C are perspective and side views of a sensor systemincluding the mounting unit 14 and electronics unit 16 attached thereto.After sensor insertion, the transcutaneous analyte sensor system 10measures a concentration of an analyte or a substance indicative of theconcentration or presence of the analyte as described above. Althoughthe examples are directed to a glucose sensor, the analyte sensor can bea sensor capable of determining the level of any suitable analyte in thebody, for example, oxygen, lactase, insulin, hormones, cholesterol,medicaments, viruses, or the like. Once the electronics unit 16 isconnected to the mounting unit 14, the sensor 32 is able to measurelevels of the analyte in the host.

Detachable connection between the mounting unit 14 and electronics unit16 provides improved manufacturability, namely, the relativelyinexpensive mounting unit 14 can be disposed of when replacing thesensor system after its usable life, while the relatively more expensiveelectronics unit 16 can be reusable with multiple sensor systems. Incertain embodiments, the electronics unit 16 is configured withprogramming, for example, initialization, calibration reset, failuretesting, or the like, each time it is initially inserted into the cavityand/or each time it initially communicates with the sensor 32. However,an integral (non-detachable) electronics unit can be configured as isappreciated by one skilled in the art.

Referring to the mechanical fit between the mounting unit 14 and theelectronics unit 16 (and/or applicator 12), a variety of mechanicaljoints are contemplated, for example, snap fit, interference fit, orslide fit. In the illustrated embodiment of FIGS. 12A to 12C, tabs 120are provided on the mounting unit 14 and/or electronics unit 16 thatenable a secure connection there between. The tabs 120 of theillustrated embodiment can improve ease of mechanical connection byproviding alignment of the mounting unit and electronics unit andadditional rigid support for force and counter force by the user (e.g.,fingers) during connection. However, other configurations with orwithout guiding tabs are contemplated, such as illustrated in FIGS. 10and 11, for example.

In some circumstances, a drift of the sensor signal can causeinaccuracies in sensor performance and/or require re-calibration of thesensor. Accordingly, it can be advantageous to provide a sealant,whereby moisture (e.g., water and water vapor) cannot substantiallypenetrate to the sensor and its connection to the electrical contacts.The sealant described herein can be used alone or in combination withthe sealing member 36 described in more detail above, to seal the sensorfrom moisture in the external environment.

Preferably, the sealant fills in holes, crevices, or other void spacesbetween the mounting unit 14 and electronics unit 16 and/or around thesensor 32 within the mounting unit 32. For example, the sealant cansurround the sensor in the portion of the sensor 32 that extends throughthe contacts 28. Additionally, the sealant can be disposed within theadditional void spaces, for example a hole 122 that extends through thesealing member 36.

Preferably, the sealant comprises a water impermeable material orcompound, for example, oil, grease, or gel. In one exemplary embodiment,the sealant comprises petroleum jelly and is used to provide a moisturebarrier surrounding the sensor 32. In one experiment, petroleum jellywas liquefied by heating, after which a sensor 32 was immersed into theliquefied petroleum jelly to coat the outer surfaces thereof. The sensorwas then assembled into a housing and inserted into a host, during whichdeployment the sensor was inserted through the electrical contacts 28and the petroleum jelly conforming therebetween. Sensors incorporatingpetroleum jelly, such as described above, when compared to sensorswithout the petroleum jelly moisture barrier exhibited less or no signaldrift over time when studied in a humid or submersed environment. Whilenot wishing to be bound by theory, it is believed that incorporation ofa moisture barrier surrounding the sensor, especially between the sensorand its associated electrical contacts, reduces or eliminates theeffects of humidity on the sensor signal. The viscosity of grease oroil-based moisture barriers allows penetration into and through evensmall cracks or crevices within the sensor and mounting unit, displacingmoisture and thereby increasing the sealing properties thereof. U.S.Pat. No. 4,259,540 and U.S. Pat. No. 5,285,513 disclose materialssuitable for use as a water impermeable material (sealant).

Referring to the electrical fit between the sensor 32 and theelectronics unit 16, contacts 28 (through which the sensor extends) areconfigured to electrically connect with mutually engaging contacts onthe electronics unit 16. A variety of configurations are contemplated;however, the mutually engaging contacts operatively connect upondetachable connection of the electronics unit 16 with the mounting unit14, and are substantially sealed from external moisture by sealingmember 36. Even with the sealing member, some circumstances may existwherein moisture can penetrate into the area surrounding the sensor 32and or contacts, for example, exposure to a humid or wet environment(e.g., caused by sweat, showering, or other environmental causes). Ithas been observed that exposure of the sensor to moisture can be a causeof baseline signal drift of the sensor over time. For example in aglucose sensor, the baseline is the component of a glucose sensor signalthat is not related to glucose (the amount of signal if no glucose ispresent), which is ideally constant over time. However, somecircumstances my exist wherein the baseline can fluctuate over time,also referred to as drift, which can be caused, for example, by changesin a host's metabolism, cellular migration surrounding the sensor,interfering species, humidity in the environment, and the like.

In some embodiments, the mounting unit is designed to provideventilation (e.g., a vent hole 124) between the exit-site and thesensor. In certain embodiments, a filter (not shown) is provided in thevent hole 124 that allows the passage of air, while preventingcontaminants from entering the vent hole 124 from the externalenvironment. While not wishing to be bound by theory, it is believedthat ventilation to the exit-site (or to the sensor 32) can reduce oreliminate trapped moisture or bacteria, which can otherwise increase thegrowth and/or lifetime of bacteria adjacent to the sensor.

In some alternative embodiments, a sealing material is provided, whichseals the needle and/or sensor from contamination of the externalenvironment during and after sensor insertion. For example, one problemencountered in conventional transcutaneous devices is infection of theexit-site of the wound. For example, bacteria or contaminants canmigrate from ex vivo, for example, any ex vivo portion of the device orthe ex vivo environment, through the exit-site of the needle/sensor, andinto the subcutaneous tissue, causing contamination and infection.Bacteria and/or contaminants can originate from handling of the device,exposed skin areas, and/or leakage from the mounting unit (external to)on the host. In many conventional transcutaneous devices, there existssome path of migration for bacteria and contaminants to the exit-site,which can become contaminated during sensor insertion or subsequenthandling or use of the device. Furthermore, in some embodiments of atranscutaneous analyte sensor, the insertion-aiding device (for example,needle) is an integral part of the mounting unit; namely, the devicestores the insertion device after insertion of the sensor, which isisolated from the exit-site (namely, point-of-entry of the sensor) afterinsertion.

Accordingly, these alternative embodiments provide a sealing material onthe mounting unit, interposed between the housing and the skin, whereinthe needle and/or sensor are adapted to extend through, and be sealedby, the sealing material. The sealing material is preferably formed froma flexible material that substantially seals around the needle/sensor.Appropriate flexible materials include malleable materials, elastomers,gels, greases, or the like (e.g., see U.S. Pat. No. 4,259,540 and U.S.Pat. No. 5,285,513). However, not all embodiments include a sealingmaterial, and in some embodiments a clearance hole or other spacesurrounding the needle and/or sensor is preferred.

In one embodiment, the base 24 of the mounting unit 14 is formed from aflexible material, for example silicone, which by its elastomericproperties seals the needle and/or sensor at the exit port 126, such asis illustrated in FIGS. 11A and 11B. Thus, sealing material can beformed as a unitary or integral piece with the back surface 25 of themounting unit 14, or with an adhesive pad 8 on the back surface of themounting unit, however alternatively can be a separate part secured tothe device. In some embodiments, the sealing material can extend throughthe exit port 126 above or below the plane of the adhesive pad surface,or the exit port 126 can comprise a septum seal such as those used inthe medical storage and disposal industries (for example, silica gelsandwiched between upper and lower seal layers, such as layerscomprising chemically inert materials such as PTFE). A variety of knownseptum seals can be implemented into the exit port of the preferredembodiments described herein. Whether the sealing material is integralwith or a separate part attached to the mounting unit 14, the exit port126 is advantageously sealed so as to reduce or eliminate the migrationof bacteria or other contaminants to or from the exit-site of the woundand/or within the mounting unit.

During use, a host or caretaker positions the mounting unit at theappropriate location on or near the host's skin and prepares for sensorinsertion. During insertion, the needle aids in sensor insertion, afterwhich the needle is retracted into the mounting unit leaving the sensorin the subcutaneous tissue. In this embodiment, the exit-port 126includes a layer of sealing material, such as a silicone membrane, thatencloses the exit-port in a configuration that protects the exit-sitefrom contamination that can migrate from the mounting unit or spacingexternal to the exit-site. Thus, when the sensor 32 and/or needle 72extend through, for example, an aperture or a puncture in the sealingmaterial, to provide communication between the mounting unit andsubcutaneous space, a seal is formed there between. Elastomeric sealingmaterials can be advantageous in some embodiments because the elasticityprovides a conforming seal between the needle/sensor and the mountingunit and/or because the elasticity provides shock-absorbing qualitiesallowing relative movement between the device and the various layers ofthe host's tissue, for example.

In some alternative embodiments, the sealing material includes abioactive agent incorporated therein. Suitable bioactive agents includethose which are known to discourage or prevent bacteria and infection,for example, anti-inflammatory, antimicrobials, antibiotics, or thelike. It is believed that diffusion or presence of a bioactive agent canaid in prevention or elimination of bacteria adjacent to the exit-site.

In practice, after the sensor 32 has been inserted into the host'stissue, and an electrical connection formed by mating the electronicsunit 16 to the mounting unit 14, the sensor measures an analyteconcentration continuously or continually, for example, at an intervalof from about fractions of a second to about 10 minutes or more.

Sensor Electronics

The following description of sensor electronics associated with theelectronics unit is applicable to a variety of continuous analytesensors, such as non-invasive, minimally invasive, and/or invasive(e.g., transcutaneous and wholly implantable) sensors. For example, thesensor electronics and data processing as well as the receiverelectronics and data processing described below can be incorporated intothe wholly implantable glucose sensor disclosed in co-pending U.S.patent application Ser. No. 10/838,912, filed May 3, 2004 and entitled“IMPLANTABLE ANALYTE SENSOR” and U.S. patent application Ser. No.10/885,476 filed Jul. 6, 2004 and entitled, “SYSTEMS AND METHODS FORMANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM”.

FIG. 13 is a block diagram that illustrates the electronics 132associated with the sensor system 10 in one embodiment. In thisembodiment, a potentiostat 134 is shown, which is operably connected toan electrode system (such as described above) and provides a voltage tothe electrodes, which biases the sensor to enable measurement of ancurrent signal indicative of the analyte concentration in the host (alsoreferred to as the analog portion). In some embodiments, thepotentiostat includes a resistor (not shown) that translates the currentinto voltage. In some alternative embodiments, a current to frequencyconverter is provided that is configured to continuously integrate themeasured current, for example, using a charge counting device.

An A/D converter 136 digitizes the analog signal into a digital signal,also referred to as “counts” for processing. Accordingly, the resultingraw data stream in counts, also referred to as raw sensor data, isdirectly related to the current measured by the potentiostat 84.

A processor module 138 includes the central control unit that controlsthe processing of the sensor electronics 132. In some embodiments, theprocessor module includes a microprocessor, however a computer systemother than a microprocessor can be used to process data as describedherein, for example an ASIC can be used for some or all of the sensor'scentral processing. The processor typically provides semi-permanentstorage of data, for example, storing data such as sensor identifier(ID) and programming to process data streams (for example, programmingfor data smoothing and/or replacement of signal artifacts such as isdescribed in co-pending U.S. patent application Ser. No. 10/648,849,filed Aug. 22, 2003, and entitled, “SYSTEMS AND METHODS FOR REPLACINGSIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”). The processoradditionally can be used for the system's cache memory, for example fortemporarily storing recent sensor data. In some embodiments, theprocessor module comprises memory storage components such as ROM, RAM,dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flashmemory, or the like.

In some embodiments, the processor module comprises a digital filter,for example, an IIR or FIR filter, configured to smooth the raw datastream from the A/D converter. Generally, digital filters are programmedto filter data sampled at a predetermined time interval (also referredto as a sample rate). In some embodiments, wherein the potentiostat isconfigured to measure the analyte at discrete time intervals, these timeintervals determine the sample rate of the digital filter. In somealternative embodiments, wherein the potentiostat is configured tocontinuously measure the analyte, for example, using acurrent-to-frequency converter as described above, the processor modulecan be programmed to request a digital value from the A/D converter at apredetermined time interval, also referred to as the acquisition time.In these alternative embodiments, the values obtained by the processorare advantageously averaged over the acquisition time due the continuityof the current measurement. Accordingly, the acquisition time determinesthe sample rate of the digital filter. In preferred embodiments, theprocessor module is configured with a programmable acquisition time,namely, the predetermined time interval for requesting the digital valuefrom the A/D converter is programmable by a user within the digitalcircuitry of the processor module. An acquisition time of from about 2seconds to about 512 seconds is preferred; however any acquisition timecan be programmed into the processor module. A programmable acquisitiontime is advantageous in optimizing noise filtration, time lag, andprocessing/battery power.

Preferably, the processor module is configured to build the data packetfor transmission to an outside source, for example, an RF transmissionto a receiver as described in more detail below. Generally, the datapacket comprises a plurality of bits that can include a sensor ID code,raw data, filtered data, and/or error detection or correction. Theprocessor module can be configured to transmit any combination of rawand/or filtered data.

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, or the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g., a number of from about 1 to about 100, or more),wherein the coefficient is multiplied by the acquisition time (orsampling rate), such as described above, to define the transmissioninterval of the data packet. Thus, in some embodiments, the transmissioninterval is programmable between about 2 seconds and about 850 minutes,more preferably between about 30 second and 5 minutes; however, anytransmission interval can be programmable or programmed into theprocessor module. However, a variety of alternative systems and methodsfor providing a programmable transmission interval can also be employed.By providing a programmable transmission interval, data transmission canbe customized to meet a variety of design criteria (e.g., reducedbattery consumption, timeliness of reporting sensor values, etc.)

Signal Detection

Conventional glucose sensors measure current in the nanoAmp range. Incontrast to conventional glucose sensors, the preferred embodiments areconfigured to measure the current flow in the picoAmp range, and in someembodiments, femtoAmps. For example, for every unit (mg/dL) of glucosemeasured, at least one picoAmp (or femtoAmp) of current is measured.Preferably, the analog portion of the A/D converter 136 is configured tocontinuously measure the current flowing at the working electrode and toconvert the current measurement to digital values representative of thecurrent. In one embodiment, the current flow is measured by a chargecounting device (e.g., a capacitor). Thus, a signal is provided, wherebya high sensitivity maximizes the signal received by a minimal amount ofmeasured hydrogen peroxide (e.g., minimal glucose requirements withoutsacrificing accuracy even in low glucose ranges), reducing thesensitivity to oxygen limitations in vivo (e.g., in oxygen-dependentglucose sensors). In sensors of certain embodiments, a resolution ashigh as about 0.003 mg/dL glucose/count can be achieved with theelectronics of the preferred embodiments, although resolutions above0.003 mg/dL glucose/count, e.g., 1 mg/dL glucose/count or higher canalso be acceptable.

Battery

A battery 144 is operably connected to the sensor electronics 132 andprovides the power for the sensor. In one embodiment, the battery is alithium manganese dioxide battery; however, any appropriately sized andpowered battery can be used (for example, AAA, nickel-cadmium,zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion,zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed).In some embodiments, the battery is rechargeable, and/or a plurality ofbatteries can be used to power the system. The sensor can betranscutaneously powered via an inductive coupling, for example. In someembodiments, a quartz crystal 96 is operably connected to the processor138 and maintains system time for the computer system as a whole, forexample for the programmable acquisition time within the processormodule.

Temperature Probe

Optional temperature probe 140 is shown, wherein the temperature probeis located on the electronics assembly or the glucose sensor itself. Thetemperature probe can be used to measure ambient temperature in thevicinity of the glucose sensor. This temperature measurement can be usedto add temperature compensation to the calculated glucose value.

RF Module

An RF module 148 is operably connected to the processor 138 andtransmits the sensor data from the sensor to a receiver within awireless transmission 150 via antenna 152. In some embodiments, a secondquartz crystal 154 provides the time base for the RF carrier frequencyused for data transmissions from the RF transceiver. In some alternativeembodiments, however, other mechanisms, such as optical, infraredradiation (IR), ultrasonic, or the like, can be used to transmit and/orreceive data.

In the RF telemetry module of the preferred embodiments, the hardwareand software are designed for low power requirements to increase thelongevity of the device (for example, to enable a life of from about 3to about 24 months, or more) with maximum RF transmittance from the invivo environment to the ex vivo environment for wholly implantablesensors (for example, a distance of from about one to ten meters ormore). Preferably, a high frequency carrier signal of from about 402 MHzto about 433 MHz is employed in order to maintain lower powerrequirements. Additionally, in wholly implantable devices, the carrierfrequency is adapted for physiological attenuation levels, which isaccomplished by tuning the RF module in a simulated in vivo environmentto ensure RF functionality after implantation; accordingly, thepreferred glucose sensor can sustain sensor function for 3 months, 6months, 12 months, or 24 months or more.

Initialization

When a sensor is first implanted into host tissue, the sensor andreceiver are initialized. This is referred to as start-up mode, andinvolves optionally resetting the sensor data and calibrating the sensor32. In selected embodiments, mating the electronics unit 16 to themounting unit triggers a start-up mode. In other embodiments, thestart-up mode is triggered by the receiver, which is described in moredetail with reference to FIG. 19, below.

Preferably, the electronics unit 16 indicates to the receiver (FIGS. 14and 15) that calibration is to be initialized (or re-initialized). Theelectronics unit 16 transmits a series of bits within a transmitted datapacket wherein a sensor code can be included in the periodictransmission of the device. The status code is used to communicatesensor status to the receiving device. The status code can be insertedinto any location in the transmitted data packet, with or without othersensor information. In one embodiment, the status code is designed to beunique or near unique to an individual sensor, which can be accomplishedusing a value that increments, decrements, or changes in some way afterthe transmitter detects that a sensor has been removed and/or attachedto the transmitter. In an alternative embodiment, the status code can beconfigured to follow a specific progression, such as a BCDinterpretation of a Gray code.

In some embodiments, the sensor electronics 132 are configured to detecta current drop to zero in the working electrode 44 associated withremoval of a sensor 32 from the host (or the electronics unit 16 fromthe mounting unit 14), which can be configured to trigger an incrementof the status code. If the incremented value reaches a maximum, it canbe designed to roll over to 0. In some embodiments, the sensorelectronics are configured to detect a voltage change cycle associatedwith removal and/or re-insertion of the sensor, which can be sensed inthe counter electrode (e.g., of a three-electrode sensor), which can beconfigured to trigger an increment of the status code.

In some embodiments, the sensor electronics 132 can be configured tosend a special value (for example, 0) that indicates that theelectronics unit is not attached when removal of the sensor (orelectronics unit) is detected. This special value can be used to triggera variety of events, for example, to halt display of analyte values.Incrementing or decrementing routines can be used to skip this specialvalue.

Electronics Unit

In some embodiments, the electronics unit 16 is configured to includeadditional contacts, which are designed to sense a specific resistance,or passive value, in the sensor system while the electronics unit isattached to the mounting unit. Preferably, these additional contacts areconfigured to detect information about a sensor, for example, whetherthe sensor is operatively connected to the mounting unit, the sensor'sID, a calibration code, or the like. For example, subsequent to sensingthe passive value, the sensor electronics can be configured to changethe sensor ID code by either mapping the value to a specific code, orinternally detecting that the code is different and adjusting the sensorID code in a predictable manner. As another example, the passive valuecan include information on parameters specific to a sensor (such as invitro sensitivity information as described elsewhere herein).

In some embodiments, the electronics unit 16 includes additionalcontacts configured to communicate with a chip disposed in the mountingunit 14. In this embodiment, the chip is designed with a unique ornear-unique signature that can be detected by the electronics unit 16and noted as different, and/or transmitted to the receiver 158 as thesensor ID code.

In some embodiments, the electronics unit 16 is inductively coupled toan RFID or similar chip in the mounting unit 14. In this embodiment, theRFID tag uniquely identifies the sensor 32 and allows the transmitter toadjust the sensor ID code accordingly and/or to transmit the uniqueidentifier to the receiver 158.

In some situations, it can be desirable to wait an amount of time afterinsertion of the sensor to allow the sensor to equilibrate in vivo, alsoreferred to as “break-in.” Accordingly, the sensor electronics can beconfigured to aid in decreasing the break-in time of the sensor byapplying different voltage settings (for example, starting with a highervoltage setting and then reducing the voltage setting) to speed theequilibration process.

In some situations, the sensor may not properly deploy, connect to, orotherwise operate as intended. Accordingly, the sensor electronics canbe configured such that if the current obtained from the workingelectrode, or the subsequent conversion of the current into digitalcounts, for example, is outside of an acceptable threshold, then thesensor is marked with an error flag, or the like. The error flag can betransmitted to the receiver to instruct the user to reinsert a newsensor, or to implement some other error correction.

The above-described detection and transmission methods can beadvantageously employed to minimize or eliminate human interaction withthe sensor, thereby minimizing human error and/or inconvenience.Additionally, the sensors of preferred embodiments do not require thatthe receiver be in proximity to the transmitter during sensor insertion.Any one or more of the above described methods of detecting andtransmitting insertion of a sensor and/or electronics unit can becombined or modified, as is appreciated by one skilled in the art.

Receiver

FIG. 14 is a perspective view of a sensor system, including wirelesscommunication between a sensor and a receiver. Preferably theelectronics unit 16 is wirelessly connected to a receiver 158 via one-or two-way RF transmissions or the like. However, a wired connection isalso contemplated. The receiver 158 provides much of the processing anddisplay of the sensor data, and can be selectively worn and/or removedat the host's convenience. Thus, the sensor system 10 can be discreetlyworn, and the receiver 158, which provides much of the processing anddisplay of the sensor data, can be selectively worn and/or removed atthe host's convenience. Particularly, the receiver 158 includesprogramming for retrospectively and/or prospectively initiating acalibration, converting sensor data, updating the calibration,evaluating received reference and sensor data, and evaluating thecalibration for the analyte sensor, such as described in more detailwith reference to co-pending U.S. patent application Ser. No.10/633,367, filed Aug. 1, 2003 and entitled, “SYSTEM AND METHODS FORPROCESSING ANALYTE SENSOR DATA.”

Receiver Electronics

FIG. 15A is a block diagram that illustrates the configuration of themedical device in one embodiment, including a continuous analyte sensor,a receiver, and an external device. In general, the analyte sensorsystem is any sensor configuration that provides an output signalindicative of a concentration of an analyte (e.g., invasive,minimally-invasive, and/or non-invasive sensors as described above). Theoutput signal is sent to a receiver 158 and received by an input module174, which is described in more detail below. The output signal istypically a raw data stream that is used to provide a useful value ofthe measured analyte concentration to a patient or a doctor, forexample. In some embodiments, the raw data stream can be continuously orperiodically algorithmically smoothed or otherwise modified to diminishoutlying points that do not accurately represent the analyteconcentration, for example due to signal noise or other signalartifacts, such as described in co-pending U.S. patent application Ser.No. 10/632,537 entitled, “SYSTEMS AND METHODS FOR REPLACING SIGNALARTIFACTS IN A GLUCOSE SENSOR DATA STREAM,” filed Aug. 22, 2003, whichis incorporated herein by reference in its entirety.

Referring again to FIG. 15A, the receiver 158, which is operativelylinked to the sensor system 10, receives a data stream from the sensorsystem 10 via the input module 174. In one embodiment, the input moduleincludes a quartz crystal operably connected to an RF transceiver (notshown) that together function to receive and synchronize data streamsfrom the sensor system 10. However, the input module 174 can beconfigured in any manner that is capable of receiving data from thesensor. Once received, the input module 174 sends the data stream to aprocessor 176 that processes the data stream, such as is described inmore detail below.

The processor 176 is the central control unit that performs theprocessing, such as storing data, analyzing data streams, calibratinganalyte sensor data, estimating analyte values, comparing estimatedanalyte values with time corresponding measured analyte values,analyzing a variation of estimated analyte values, downloading data, andcontrolling the user interface by providing analyte values, prompts,messages, warnings, alarms, or the like. The processor includes hardwareand software that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing.

Preferably, the input module 174 or processor module 176 performs aCyclic Redundancy Check (CRC) to verify data integrity, with or withouta method of recovering the data if there is an error. In someembodiments, error correction techniques such as those that use Hammingcodes or Reed-Solomon encoding/decoding methods are employed to correctfor errors in the data stream. In one alternative embodiment, aniterative decoding technique is employed, wherein the decoding isprocessed iteratively (e.g., in a closed loop) to determine the mostlikely decoded signal. This type of decoding can allow for recovery of asignal that is as low as 0.5 dB above the noise floor, which is incontrast to conventional non-iterative decoding techniques (such asReed-Solomon), which requires approximately 3 dB or about twice thesignal power to recover the same signal (e.g., a turbo code).

An output module 178, which is integral with and/or operativelyconnected with the processor 176, includes programming for generatingoutput based on the data stream received from the sensor system 10 andits processing incurred in the processor 176. In some embodiments,output is generated via a user interface 160.

The user interface 160 comprises a keyboard 162, speaker 164, vibrator166, backlight 168, liquid crystal display (LCD) screen 170, and one ormore buttons 172. The components that comprise the user interface 160include controls to allow interaction of the user with the receiver. Thekeyboard 162 can allow, for example, input of user information abouthimself/herself, such as mealtime, exercise, insulin administration,customized therapy recommendations, and reference analyte values. Thespeaker 164 can produce, for example, audible signals or alerts forconditions such as present and/or estimated hyperglycemic orhypoglycemic conditions in a person with diabetes. The vibrator 166 canprovide, for example, tactile signals or alerts for reasons such asdescribed with reference to the speaker, above. The backlight 168 can beprovided, for example, to aid the user in reading the LCD 170 in lowlight conditions. The LCD 170 can be provided, for example, to providethe user with visual data output, such as is described in co-pendingU.S. patent application Ser. No. 11/007,920 filed Dec. 8, 2004 andentitled “SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSORS.” FIGS. 15Bto 15D illustrate some additional visual displays that can be providedon the screen 170. In some embodiments, the LCD is a touch-activatedscreen, enabling each selection by a user, for example, from a menu onthe screen. The buttons 172 can provide for toggle, menu selection,option selection, mode selection, and reset, for example. In somealternative embodiments, a microphone can be provided to allow forvoice-activated control.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, or the like. Additionally, prompts can be displayed to guide theuser through calibration or trouble-shooting of the calibration.

Additionally, data output from the output module 178 can provide wiredor wireless, one-way or two-way communication between the receiver 158and an external device 180. The external device 180 can be any devicethat wherein interfaces or communicates with the receiver 158. In someembodiments, the external device 180 is a computer, and the receiver 158is able to download historical data for retrospective analysis by thepatient or physician, for example. In some embodiments, the externaldevice 180 is a modem or other telecommunications station, and thereceiver 158 is able to send alerts, warnings, emergency messages, orthe like, via telecommunication lines to another party, such as a doctoror family member. In some embodiments, the external device 180 is aninsulin pen, and the receiver 158 is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pen. Insome embodiments, the external device 180 is an insulin pump, and thereceiver 158 is able to communicate therapy recommendations, such asinsulin amount and time to the insulin pump. The external device 180 caninclude other technology or medical devices, for example pacemakers,implanted analyte sensor patches, other infusion devices, telemetrydevices, or the like.

The user interface 160, including keyboard 162, buttons 172, amicrophone (not shown), and the external device 180, can be configuredto allow input of data. Data input can be helpful in obtaininginformation about the patient (for example, meal time, exercise, or thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, or the like), and downloading softwareupdates, for example. Keyboard, buttons, touch-screen, and microphoneare all examples of mechanisms by which a user can input data directlyinto the receiver. A server, personal computer, personal digitalassistant, insulin pump, and insulin pen are examples of externaldevices that can provide useful information to the receiver. Otherdevices internal or external to the sensor that measure other aspects ofa patient's body (for example, temperature sensor, accelerometer, heartrate monitor, oxygen monitor, or the like) can be used to provide inputhelpful in data processing. In one embodiment, the user interface canprompt the patient to select an activity most closely related to theirpresent activity, which can be helpful in linking to an individual'sphysiological patterns, or other data processing. In another embodiment,a temperature sensor and/or heart rate monitor can provide informationhelpful in linking activity, metabolism, and glucose excursions of anindividual. While a few examples of data input have been provided here,a variety of information can be input, which can be helpful in dataprocessing.

FIG. 15B is an illustration of an LCD screen 170 showing continuous andsingle point glucose information in the form of a trend graph 184 and asingle numerical value 186. The trend graph shows upper and lowerboundaries 182 representing a target range between which the host shouldmaintain his/her glucose values. Preferably, the receiver is configuredsuch that these boundaries 182 can be configured or customized by auser, such as the host or a care provider. By providing visualboundaries 182, in combination with continuous analyte values over time(e.g., a trend graph 184), a user may better learn how to controlhis/her analyte concentration (e.g., a person with diabetes may betterlearn how to control his/her glucose concentration) as compared tosingle point (single numerical value 186) alone. Although FIG. 15Billustrates a 1-hour trend graph (e.g., depicted with a time range 188of 1-hour), a variety of time ranges can be represented on the screen170, for example, 3-hour, 9-hour, 1-day, and the like.

FIG. 15C is an illustration of an LCD screen 170 showing a low alertscreen that can be displayed responsive to a host's analyteconcentration falling below a lower boundary (see boundaries 182). Inthis exemplary screen, a host's glucose concentration has fallen to 55mg/dL, which is below the lower boundary set in FIG. 15B, for example.The arrow 190 represents the direction of the analyte trend, forexample, indicating that the glucose concentration is continuing todrop. The annotation 192 (“LOW”) is helpful in immediately and clearlyalerting the host that his/her glucose concentration has dropped below apreset limit, and what may be considered to be a clinically safe value,for example. FIG. 15D is an illustration of an LCD screen 170 showing ahigh alert screen that can be displayed responsive to a host's analyteconcentration rising above an upper boundary (see boundaries 182). Inthis exemplary screen, a host's glucose concentration has risen to 200mg/dL, which is above a boundary set by the host, thereby triggering thehigh alert screen. The arrow 190 represents the direction of the analytetrend, for example, indicating that the glucose concentration iscontinuing to rise. The annotation 192 (“HIGH”) is helpful inimmediately and clearly alerting the host that his/her glucoseconcentration has above a preset limit, and what may be considered to bea clinically safe value, for example.

Although a few exemplary screens are depicted herein, a variety ofscreens can be provided for illustrating any of the informationdescribed in the preferred embodiments, as well as additionalinformation. A user can toggle between these screens (e.g., usingbuttons 172) and/or the screens can be automatically displayedresponsive to programming within the receiver 158, and can besimultaneously accompanied by another type of alert (audible or tactile,for example).

Algorithms

FIG. 16A provides a flow chart 200 that illustrates the initialcalibration and data output of the sensor data in one embodiment,wherein calibration is responsive to reference analyte data. Initialcalibration, also referred to as start-up mode, occurs at theinitialization of a sensor, for example, the first time an electronicsunit is used with a particular sensor. In certain embodiments, start-upcalibration is triggered when the system determines that it can nolonger remain in normal or suspended mode, which is described in moredetail with reference to FIG. 19.

Calibration of an analyte sensor comprises data processing that convertssensor data signal into an estimated analyte measurement that ismeaningful to a user. Accordingly, a reference analyte value is used tocalibrate the data signal from the analyte sensor.

At block 202, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from the sensor 32via the receiver 158, which can be in wired or wireless communicationwith the sensor 32. The sensor data point(s) can be smoothed (filtered)in certain embodiments using a filter, for example, a finite impulseresponse (FIR) or infinite impulse response (IIR) filter. During theinitialization of the sensor, prior to initial calibration, the receiverreceives and stores the sensor data, however it can be configured to notdisplay any data to the user until initial calibration and, optionally,stabilization of the sensor has been established. In some embodiments,the data stream can be evaluated to determine sensor break-in(equilibration of the sensor in vitro or in vivo).

At block 204, a reference data receiving module, also referred to as thereference input module, receives reference data from a reference analytemonitor, including one or more reference data points. In one embodiment,the reference analyte points can comprise results from a self-monitoredblood analyte test (e.g., finger stick test). For example, the user canadminister a self-monitored blood analyte test to obtain an analytevalue (e.g., point) using any known analyte sensor, and then enter thenumeric analyte value into the computer system. Alternatively, aself-monitored blood analyte test is transferred into the computersystem through a wired or wireless connection to the receiver (e.g.computer system) so that the user simply initiates a connection betweenthe two devices, and the reference analyte data is passed or downloadedbetween the self-monitored blood analyte test and the receiver. In yetanother embodiment, the self-monitored analyte test (e.g., SMBG) isintegral with the receiver so that the user simply provides a bloodsample to the receiver, and the receiver runs the analyte test todetermine a reference analyte value. Co-pending U.S. patent applicationSer. No. 10/991,966, filed on Nov. 17, 2004 and entitled “INTEGRATEDRECEIVER FOR CONTINUOUS ANALYTE SENSOR” describes some systems andmethods for integrating a reference analyte monitor into a receiver fora continuous analyte sensor.

In some alternative embodiments, the reference data is based on sensordata from another substantially continuous analyte sensor, e.g., atranscutaneous analyte sensor described herein, or another type ofsuitable continuous analyte sensor. In an embodiment employing a seriesof two or more transcutaneous (or other continuous) sensors, the sensorscan be employed so that they provide sensor data in discrete oroverlapping periods. In such embodiments, the sensor data from onecontinuous sensor can be used to calibrate another continuous sensor, orbe used to confirm the validity of a subsequently employed continuoussensor.

In some embodiments, reference data can be subjected to “outlierdetection” wherein the accuracy of a received reference analyte data isevaluated as compared to time-corresponding sensor data. In oneembodiment, the reference data is compared to the sensor data on amodified Clarke Error Grid (e.g., a test similar to the Clarke ErrorGrid except the boundaries between the different regions are modifiedslightly) to determine if the data falls within a predeterminedthreshold. If the data is not within the predetermined threshold, thenthe receiver can be configured to request additional reference analytedata. If the additional reference analyte data confirms (e.g., closelycorrelates to) the first reference analyte data, then the first andsecond reference values are assumed to be accurate and calibration ofthe sensor is adjusted or re-initialized. Alternatively, if the secondreference analyte value falls within the predetermined threshold, thenthe first reference analyte value is assumed to be an outlier and thesecond reference analyte value is used by the algorithm(s) instead. Inone alternative embodiments of outlier detection, projection is used toestimate an expected analyte value, which is compared with the actualvalue and a delta evaluated for substantial correspondence. However,other methods of outlier detection are possible.

Certain acceptability parameters can be set for reference valuesreceived from the user. For example, in one embodiment, the receiver canbe configured to only accept reference analyte values of from about 40mg/dL to about 400 mg/dL.

At block 206, a data matching module, also referred to as the processormodule, matches reference data (e.g., one or more reference analyte datapoints) with substantially time corresponding sensor data (e.g., one ormore sensor data points) to provide one or more matched data pairs. Onereference data point can be matched to one time corresponding sensordata point to form a matched data pair. Alternatively, a plurality ofreference data points can be averaged (e.g., equally or non-equallyweighted average, mean-value, median, or the like) and matched to onetime corresponding sensor data point to form a matched data pair, onereference data point can be matched to a plurality of time correspondingsensor data points averaged to form a matched data pair, or a pluralityof reference data points can be averaged and matched to a plurality oftime corresponding sensor data points averaged to form a matched datapair.

In one embodiment, time corresponding sensor data comprises one or moresensor data points that occur from about 0 minutes to about 20 minutesafter the reference analyte data time stamp (e.g., the time that thereference analyte data is obtained). In one embodiment, a 5-minute timedelay is chosen to compensate for a system time-lag (e.g., the timenecessary for the analyte to diffusion through a membrane(s) of ananalyte sensor). In alternative embodiments, the time correspondingsensor value can be greater than or less than that of theabove-described embodiment, for example ±60 minutes. Variability in timecorrespondence of sensor and reference data can be attributed to, forexample, a longer or shorter time delay introduced by the data smoothingfilter, or if the configuration of the analyte sensor incurs a greateror lesser physiological time lag.

In some implementations of the sensor, the reference analyte data isobtained at a time that is different from the time that the data isinput into the receiver. Accordingly, the “time stamp” of the referenceanalyte (e.g., the time at which the reference analyte value wasobtained) is not the same as the time at which the receiver obtained thereference analyte data. Therefore, some embodiments include a time stamprequirement that ensures that the receiver stores the accurate timestamp for each reference analyte value, that is, the time at which thereference value was actually obtained from the user.

In certain embodiments, tests are used to evaluate the best-matched pairusing a reference data point against individual sensor values over apredetermined time period (e.g., about 30 minutes). In one suchembodiment, the reference data point is matched with sensor data pointsat 5-minute intervals and each matched pair is evaluated. The matchedpair with the best correlation can be selected as the matched pair fordata processing. In some alternative embodiments, matching a referencedata point with an average of a plurality of sensor data points over apredetermined time period can be used to form a matched pair.

At block 208, a calibration set module, also referred to as theprocessor module, forms an initial calibration set from a set of one ormore matched data pairs, which are used to determine the relationshipbetween the reference analyte data and the sensor analyte data. Thematched data pairs, which make up the initial calibration set, can beselected according to predetermined criteria. The criteria for theinitial calibration set can be the same as, or different from, thecriteria for the updated calibration sets. In certain embodiments, thenumber (n) of data pair(s) selected for the initial calibration set isone. In other embodiments, n data pairs are selected for the initialcalibration set wherein n is a function of the frequency of the receivedreference data points. In various embodiments, two data pairs make upthe initial calibration set or six data pairs make up the initialcalibration set. In an embodiment wherein a substantially continuousanalyte sensor provides reference data, numerous data points are used toprovide reference data from more than 6 data pairs (e.g., dozens or evenhundreds of data pairs). In one exemplary embodiment, a substantiallycontinuous analyte sensor provides 288 reference data points per day(every five minutes for twenty-four hours), thereby providing anopportunity for a matched data pair 288 times per day, for example.While specific numbers of matched data pairs are referred to in thepreferred embodiments, any suitable number of matched data pairs per agiven time period can be employed.

In certain embodiments, the data pairs are selected only within acertain analyte value threshold, for example wherein the referenceanalyte value is from about 40 mg/dL to about 400 mg/dL. In certainembodiments, the data pairs that form the initial calibration set areselected according to their time stamp, for example, by waiting apredetermined “break-in” time period after implantation, the stabilityof the sensor data can be increased. In certain embodiments, the datapairs that form the initial calibration set are spread out over apredetermined time period, for example, a period of two hours or more.In certain embodiments, the data pairs that form the initial calibrationset are spread out over a predetermined glucose range, for example,spread out over a range of at least 90 mg/dL or more.

At block 210, a conversion function module, also referred to as theprocessor module, uses the calibration set to create a conversionfunction. The conversion function substantially defines the relationshipbetween the reference analyte data and the analyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form thecalibration set, a linear least squares regression is used to calculatethe conversion function; for example, this regression calculates a slopeand an offset using the equation y=m×+b. A variety of regression orother conversion schemes can be implemented herein.

In some alternative embodiments, the sensor is calibrated with asingle-point through the use of a dual-electrode system to simplifysensor calibration. In one such dual-electrode system, a first electrodefunctions as a hydrogen peroxide sensor including a membrane systemcontaining glucose-oxidase disposed thereon, which operates as describedherein. A second electrode is a hydrogen peroxide sensor that isconfigured similar to the first electrode, but with a modified membranesystem (with the enzyme domain removed, for example). This secondelectrode provides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. Co-pending U.S.patent application Ser. No. 11/004,561 filed Dec. 3, 2004 and entitled,“CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR” describessystems and methods for subtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, a regression equation y=m×+b is used tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g., obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g., priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)), then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed=0, for example with adual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g., by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

If the slope and/or baseline fall within the predetermined acceptableboundaries, then the regression is considered acceptable and processingcontinues to the next step (e.g., block 212). Alternatively, if theslope and/or baseline fall outside the predetermined acceptableboundaries, steps can be taken to either correct the regression orfail-safe such that a system will not process or display errant data.This can be useful in situations wherein regression results in errantslope or baseline values. For example, when points (matched pairs) usedfor regression are too close in value, the resulting regressionstatistically is less accurate than when the values are spread fartherapart. As another example, a sensor that is not properly deployed or isdamaged during deployment can yield a skewed or errant baseline signal.

FIG. 16B is a graph that illustrates one example of using priorinformation for slope and baseline. The x-axis represents referenceglucose data (blood glucose) from a reference glucose source in mg/dL;the y-axis represents sensor data from a transcutaneous glucose sensorof the preferred embodiments in counts. An upper boundary line 215 is aregression line that represents an upper boundary of “acceptability” inthis example; the lower boundary line 216 is a regression line thatrepresents a lower boundary of “acceptability” in this example. Theboundary lines 215, 216 were obtained from retrospective analysis of invivo sensitivities and baselines of glucose sensors as described in thepreferred embodiments.

A plurality of matched data pairs 217 represents data pairs in acalibration set obtained from a glucose sensor as described in thepreferred embodiments. The matched data pairs are plotted according totheir sensor data and time-corresponding reference glucose data. Aregression line 218 represents the result of regressing the matched datapairs 217 using least squares regression. In this example, theregression line falls within the upper and lower boundaries 215, 216indicating that the sensor calibration is acceptable.

However, if the slope and/or baseline had fallen outside thepredetermined acceptable boundaries, which would be illustrated in thisgraph by a line that crosses the upper and/or lower boundaries 215, 216,then the system is configured to assume a baseline value and re-run theregression (or a modified version of the regression) with the assumedbaseline, wherein the assumed baseline value is derived from in vivo orin vitro testing. Subsequently, the newly derived slope and baseline areagain tested to determine whether they fall within the predeterminedacceptable boundaries. Similarly, the processing continues in responseto the results of the boundary test. In general, for a set of matchedpairs (e.g., calibration set), regression lines with higher slope(sensitivity) have a lower baseline and regression lines with lowerslope (sensitivity) have a higher baseline. Accordingly, the step ofassuming a baseline and testing against boundaries can be repeated usinga variety of different assumed baselines based on the baseline,sensitivity, in vitro testing, and/or in vivo testing. For example, if aboundary test fails due to high sensitivity, then a higher baseline isassumed and the regression re-run and boundary-tested. It is preferredthat after about two iterations of assuming a baseline and/orsensitivity and running a modified regression, the system assumes anerror has occurred (if the resulting regression lines fall outside theboundaries) and fail-safe. The term “fail-safe” includes modifying thesystem processing and/or display of data responsive to a detected erroravoid reporting of inaccurate or clinically irrelevant analyte values.

In these various embodiments utilizing an additional electrode, priorinformation (e.g., in vitro or in vivo testing), signal processing, orother information for assisting in the calibration process can be usedalone or in combination to reduce or eliminate the dependency of thecalibration on reference analyte values obtained by the host.

At block 212, a sensor data transformation module uses the conversionfunction to transform sensor data into substantially real-time analytevalue estimates, also referred to as calibrated data, or convertedsensor data, as sensor data is continuously (or intermittently) receivedfrom the sensor. For example, the sensor data, which can be provided tothe receiver in “counts,” is translated in to estimate analyte value(s)in mg/dL. In other words, the offset value at any given point in timecan be subtracted from the raw value (e.g., in counts) and divided bythe slope to obtain the estimate analyte value:

${{mg}\text{/}{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In some alternative embodiments, the sensor and/or reference analytevalues are stored in a database for retrospective analysis.

At block 214, an output module provides output to the user via the userinterface. The output is representative of the estimated analyte value,which is determined by converting the sensor data into a meaningfulanalyte value. User output can be in the form of a numeric estimatedanalyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

In some embodiments, annotations are provided on the graph; for example,bitmap images are displayed thereon, which represent events experiencedby the host. For example, information about meals, insulin, exercise,sensor insertion, sleep, and the like, can be obtained by the receiver(by user input or receipt of a transmission from another device) anddisplayed on the graphical representation of the host's glucose overtime. It is believed that illustrating a host's life events matched witha host's glucose concentration over time can be helpful in educating thehost to his or her metabolic response to the various events.

In yet another alternative embodiment, the sensor utilizes one or moreadditional electrodes to measure an additional analyte. Suchmeasurements can provide a baseline or sensitivity measurement for usein calibrating the sensor. Furthermore, baseline and/or sensitivitymeasurements can be used to trigger events such as digital filtering ofdata or suspending display of data, all of which are described in moredetail in co-pending U.S. patent application Ser. No. 11/004,561, filedDec. 3, 2004 and entitled, “CALIBRATION TECHNIQUES FOR A CONTINUOUSANALYTE SENSOR.”

FIG. 17 provides a flow chart 220 that illustrates the evaluation ofreference and/or sensor data for statistical, clinical, and/orphysiological acceptability in one embodiment. Although someacceptability tests are disclosed herein, any known statistical,clinical, physiological standards and methodologies can be applied toevaluate the acceptability of reference and sensor analyte data.

One cause for discrepancies in reference and sensor data is asensitivity drift that can occur over time, when a sensor is insertedinto a host and cellular invasion of the sensor begins to blocktransport of the analyte to the sensor, for example. Therefore, it canbe advantageous to validate the acceptability of converted sensor dataagainst reference analyte data, to determine if a drift of sensitivityhas occurred and whether the calibration should be updated.

In one embodiment, the reference analyte data is evaluated with respectto substantially time corresponding converted sensor data to determinethe acceptability of the matched pair. For example, clinicalacceptability considers a deviation between time corresponding analytemeasurements (for example, data from a glucose sensor and data from areference glucose monitor) and the risk (for example, to the decisionmaking of a person with diabetes) associated with that deviation basedon the glucose value indicated by the sensor and/or reference data.Evaluating the clinical acceptability of reference and sensor analytedata, and controlling the user interface dependent thereon, can minimizeclinical risk. Preferably, the receiver evaluates clinical acceptabilityeach time reference data is obtained.

After initial calibration, such as is described in more detail withreference to FIG. 16, the sensor data receiving module 222 receivessubstantially continuous sensor data (e.g., a data stream) via areceiver and converts that data into estimated analyte values. As usedherein, the term “substantially continuous” is a broad term and is usedin its ordinary sense, without limitation, to refer to a data stream ofindividual measurements taken at time intervals (e.g., time-spaced)ranging from fractions of a second up to, e.g., 1, 2, or 5 minutes ormore. As sensor data is continuously converted, it can be occasionallyrecalibrated in response to changes in sensor sensitivity (drift), forexample. Initial calibration and re-calibration of the sensor require areference analyte value. Accordingly, the receiver can receive referenceanalyte data at any time for appropriate processing.

At block 222, the reference data receiving module, also referred to asthe reference input module, receives reference analyte data from areference analyte monitor. In one embodiment, the reference datacomprises one analyte value obtained from a reference monitor. In somealternative embodiments however, the reference data includes a set ofanalyte values entered by a user into the interface and averaged byknown methods, such as are described elsewhere herein. In somealternative embodiments, the reference data comprises a plurality ofanalyte values obtained from another continuous analyte sensor.

The reference data can be pre-screened according to environmental andphysiological issues, such as time of day, oxygen concentration,postural effects, and patient-entered environmental data. In oneexemplary embodiment, wherein the sensor comprises an implantableglucose sensor, an oxygen sensor within the glucose sensor is used todetermine if sufficient oxygen is being provided to successfullycomplete the enzyme and electrochemical reactions for accurate glucosesensing. In another exemplary embodiment, the patient is prompted toenter data into the user interface, such as meal times and/or amount ofexercise, which can be used to determine likelihood of acceptablereference data. In yet another exemplary embodiment, the reference datais matched with time-corresponding sensor data, which is then evaluatedon a modified clinical error grid to determine its clinicalacceptability.

Some evaluation data, such as described in the paragraph above, can beused to evaluate an optimum time for reference analyte measurement.Correspondingly, the user interface can then prompt the user to providea reference data point for calibration within a given time period.Consequently, because the receiver proactively prompts the user duringoptimum calibration times, the likelihood of error due to environmentaland physiological limitations can decrease and consistency andacceptability of the calibration can increase.

At block 224, the evaluation module, also referred to as acceptabilitymodule, evaluates newly received reference data. In one embodiment, theevaluation module evaluates the clinical acceptability of newly receivedreference data and time corresponding converted sensor data (new matcheddata pair). In one embodiment, a clinical acceptability evaluationmodule 224 matches the reference data with a substantially timecorresponding converted sensor value, and determines the Clarke ErrorGrid coordinates. In this embodiment, matched pairs that fall within theA and B regions of the Clarke Error Grid are considered clinicallyacceptable, while matched pairs that fall within the C, D, and E regionsof the Clarke Error Grid are not considered clinically acceptable.

A variety of other known methods of evaluating clinical acceptabilitycan be utilized. In one alternative embodiment, the Consensus Grid isused to evaluate the clinical acceptability of reference and sensordata. In another alternative embodiment, a mean absolute differencecalculation can be used to evaluate the clinical acceptability of thereference data. In another alternative embodiment, the clinicalacceptability can be evaluated using any relevant clinical acceptabilitytest, such as a known grid (e.g., Clarke Error or Consensus), andadditional parameters, such as time of day and/or the increase ordecreasing trend of the analyte concentration. In another alternativeembodiment, a rate of change calculation can be used to evaluateclinical acceptability. In yet another alternative embodiment, whereinthe received reference data is in substantially real time, theconversion function could be used to predict an estimated glucose valueat a time corresponding to the time stamp of the reference analyte value(this can be required due to a time lag of the sensor data such asdescribed elsewhere herein). Accordingly, a threshold can be set for thepredicted estimated glucose value and the reference analyte valuedisparity, if any. In some alternative embodiments, the reference datais evaluated for physiological and/or statistical acceptability asdescribed in more detail elsewhere herein.

At decision block 226, results of the evaluation are assessed. Ifacceptability is determined, then processing continues to block 228 tore-calculate the conversion function using the new matched data pair inthe calibration set.

At block 228, the conversion function module re-creates the conversionfunction using the new matched data pair associated with the newlyreceived reference data. In one embodiment, the conversion functionmodule adds the newly received reference data (e.g., including thematched sensor data) into the calibration set, and recalculates theconversion function accordingly. In alternative embodiments, theconversion function module displaces the oldest, and/or least concordantmatched data pair from the calibration set, and recalculates theconversion function accordingly.

At block 230, the sensor data transformation module uses the newconversion function (from block 228) to continually (or intermittently)convert sensor data into estimated analyte values, also referred to ascalibrated data, or converted sensor data, such as is described in moredetail above.

At block 232, an output module provides output to the user via the userinterface. The output is representative of the estimated analyte value,which is determined by converting the sensor data into a meaningfulanalyte value. User output can be in the form of a numeric estimatedanalyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

If, however, acceptability is determined at decision block 226 asnegative (unacceptable), then the processing progresses to block 234 toadjust the calibration set. In one embodiment of a calibration setadjustment, the conversion function module removes one or more of theoldest matched data pair(s) and recalculates the conversion functionaccordingly. In an alternative embodiment, the conversion functionmodule removes the least concordant matched data pair from thecalibration set, and recalculates the conversion function accordingly.

At block 236, the conversion function module re-creates the conversionfunction using the adjusted calibration set. While not wishing to bebound by theory, it is believed that removing the least concordantand/or oldest matched data pair(s) from the calibration set can reduceor eliminate the effects of sensor sensitivity drift over time,adjusting the conversion function to better represent the currentsensitivity of the sensor.

At block 224, the evaluation module re-evaluates the acceptability ofnewly received reference data with time corresponding converted sensordata that has been converted using the new conversion function (block236). The flow continues to decision block 238 to assess the results ofthe evaluation, such as described with reference to decision block 226,above. If acceptability is determined, then processing continues toblock 230 to convert sensor data using the new conversion function andcontinuously display calibrated sensor data on the user interface.

If, however, acceptability is determined at decision block 226 asnegative, then the processing loops back to block 234 to adjust thecalibration set once again. This process can continue until thecalibration set is no longer sufficient for calibration, for example,when the calibration set includes only one or no matched data pairs withwhich to create a conversion function. In this situation, the system canreturn to the initial calibration or start-up mode, which is describedin more detail with reference to FIGS. 16 and 19, for example.Alternatively, the process can continue until inappropriate matched datapairs have been sufficiently purged and acceptability is positivelydetermined.

In alternative embodiments, the acceptability is determined by a qualityevaluation, for example, calibration quality can be evaluated bydetermining the statistical association of data that forms thecalibration set, which determines the confidence associated with theconversion function used in calibration and conversion of raw sensordata into estimated analyte values. See, e.g., co-pending U.S. patentapplication Ser. No. 10/633,367 filed Aug. 1, 2003 entitled, “SYSTEM ANDMETHODS FOR PROCESSING ANALYTE SENSOR DATA.”

Alternatively, each matched data pair can be evaluated based on clinicalor statistical acceptability such as described above; however, when amatched data pair does not pass the evaluation criteria, the system canbe configured to ask for another matched data pair from the user. Inthis way, a secondary check can be used to determine whether the erroris more likely due to the reference glucose value or to the sensorvalue. If the second reference glucose value substantially correlates tothe first reference glucose value, it can be presumed that the referenceglucose value is more accurate and the sensor values are errant. Somereasons for errancy of the sensor values include a shift in the baselineof the signal or noise on the signal due to low oxygen, for example. Insuch cases, the system can be configured to re-initiate calibrationusing the secondary reference glucose value. If, however, the referenceglucose values do not substantially correlate, it can be presumed thatthe sensor glucose values are more accurate and the reference glucosevalues eliminated from the algorithm.

FIG. 18 provides is a flow chart 250 that illustrates the evaluation ofcalibrated sensor data for aberrant values in one embodiment. Althoughsensor data are typically accurate and reliable, it can be advantageousto perform a self-diagnostic check of the calibrated sensor data priorto displaying the analyte data on the user interface.

One reason for anomalies in calibrated sensor data includes transientevents, such as local ischemia at the implant site, which cantemporarily cause erroneous readings caused by insufficient oxygen toreact with the analyte. Accordingly, the flow chart 190 illustrates oneself-diagnostic check that can be used to catch erroneous data beforedisplaying it to the user.

At block 252, a sensor data receiving module, also referred to as thesensor data module, receives new sensor data from the sensor.

At block 24, the sensor data transformation module continuously (orintermittently) converts new sensor data into estimated analyte values,also referred to as calibrated data.

At block 256, a self-diagnostic module compares the new calibratedsensor data with previous calibrated sensor data, for example, the mostrecent calibrated sensor data value. In comparing the new and previoussensor data, a variety of parameters can be evaluated. In oneembodiment, the rate of change and/or acceleration (or deceleration) ofchange of various analytes, which have known physiological limits withinthe body, and sensor data can be evaluated accordingly. For example, alimit can be set to determine if the new sensor data is within aphysiologically feasible range, indicated by a rate of change from theprevious data that is within known physiological (and/or statistical)limits. Similarly, any algorithm that predicts a future value of ananalyte can be used to predict and then compare an actual value to atime corresponding predicted value to determine if the actual valuefalls within a statistically and/or clinically acceptable range based onthe predictive algorithm, for example. In certain embodiments,identifying a disparity between predicted and measured analyte data canbe used to identify a shift in signal baseline responsive to anevaluated difference between the predicted data and time-correspondingmeasured data. In some alternative embodiments, a shift in signalbaseline and/or sensitivity can be determined by monitoring a change inthe conversion function; namely, when a conversion function isre-calculated using the equation y=mx+b, a change in the values of m(sensitivity) or b (baseline) above a pre-selected “normal” threshold,can be used to trigger a fail-safe or further diagnostic evaluation.

Although the above-described self-diagnostics are generally employedwith calibrated sensor data, some alternative embodiments arecontemplated that check for aberrancy of consecutive sensor values priorto sensor calibration, for example, on the raw data stream and/or afterfiltering of the raw data stream. In certain embodiments, anintermittent or continuous signal-to-noise measurement can be evaluatedto determine aberrancy of sensor data responsive to a signal-to-noiseratio above a set threshold. In certain embodiments, signal residuals(e.g., by comparing raw and filtered data) can be intermittently orcontinuously analyzed for noise above a set threshold. In certainembodiments, pattern recognition can be used to identify noiseassociated with physiological conditions, such as low oxygen (see, e.g.,co-pending U.S. application Ser. No. 10/648,849 filed Aug. 22, 2003 andentitled, “SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN AGLUCOSE SENSOR DATA STREAM”), or other known signal aberrancies.Accordingly, in these embodiments, the system can be configured, inresponse to aberrancies in the data stream, to trigger signalestimation, adaptively filter the data stream according to theaberrancy, or the like, as described in more detail in the above citedco-pending U.S. application Ser. No. 10/648,849.

In another embodiment, reference analyte values are processed todetermine a level of confidence, wherein reference analyte values arecompared to their time-corresponding calibrated sensor values andevaluated for clinical or statistical accuracy. In yet anotheralternative embodiment, new and previous reference analyte data arecompared in place of or in addition to sensor data. In general, thereexist known patterns and limitations of analyte values that can be usedto diagnose certain anomalies in raw or calibrated sensor and/orreference analyte data.

Block 193 describes additional systems and methods that can by utilizedby the self-diagnostics module of the preferred embodiments.

At decision block 258, the system determines whether the comparisonreturned aberrant values. In one embodiment, the slope (rate of change)between the new and previous sensor data is evaluated, wherein valuesgreater than +/−10, 15, 20, 25, or 30% or more change and/or +/−2, 3, 4,5, 6 or more mg/dL/min, more preferably +/−4 mg/dL/min, rate of changeare considered aberrant. In certain embodiments, other knownphysiological parameters can be used to determine aberrant values.However, a variety of comparisons and limitations can be set.

At block 260, if the values are not found to be aberrant, the sensordata transformation module continuously (or intermittently) convertsreceived new sensor data into estimated analyte values, also referred toas calibrated data.

At block 262, if the values are found to be aberrant, the system goesinto a suspended mode, also referred to as fail-safe mode in someembodiments, which is described in more detail below with reference toFIG. 19. In general, suspended mode suspends display of calibratedsensor data and/or insertion of matched data pairs into the calibrationset. Preferably, the system remains in suspended mode until receivedsensor data is not found to be aberrant. In certain embodiments, a timelimit or threshold for suspension is set, after which system and/or userinteraction can be required, for example, requesting additionalreference analyte data, replacement of the electronics unit, and/orreset.

In some alternative embodiments, in response to a positive determinationof aberrant value(s), the system can be configured to estimate one ormore glucose values for the time period during which aberrant valuesexist. Signal estimation generally refers to filtering, data smoothing,augmenting, projecting, and/or other methods for estimating glucosevalues based on historical data, for example. In one implementation ofsignal estimation, physiologically feasible values are calculated basedon the most recent glucose data, and the aberrant values are replacedwith the closest physiologically feasible glucose values. See alsoco-pending U.S. application Ser. No. 10/633,367 filed Aug. 1, 2003entitled, “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA,” U.S.application Ser. No. 10/648,849 filed Aug. 22, 2003 and entitled,“SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSORDATA STREAM,” and U.S. Provisional Patent Application No. 60/528,382filed Dec. 9, 2003 entitled, “SIGNAL PROCESSING FOR CONTINUOUS ANALYTESENSORS.”

FIG. 19 provides a flow chart 280 that illustrates a self-diagnostic ofsensor data in one embodiment. Although reference analyte values canuseful for checking and calibrating sensor data, self-diagnosticcapabilities of the sensor provide for a fail-safe for displaying sensordata with confidence and enable minimal user interaction (for example,requiring reference analyte values only as needed).

At block 282, a sensor data receiving module, also referred to as thesensor data module, receives new sensor data from the sensor.

At block 284, the sensor data transformation module continuously (orintermittently) converts received new sensor data into estimated analytevalues, also referred to as calibrated data.

At block 286, a self-diagnostics module, also referred to as a fail-safemodule, performs one or more calculations to determine the accuracy,reliability, and/or clinical acceptability of the sensor data. Someexamples of the self-diagnostics module are described above, withreference block 256. The self-diagnostics module can be furtherconfigured to run periodically (e.g., intermittently or in response to atrigger), for example, on raw data, filtered data, calibrated data,predicted data, and the like.

In certain embodiments, the self-diagnostics module evaluates an amountof time since sensor insertion into the host, wherein a threshold is setfor the sensor's usable life, after which time period the sensor isconsidered to be unreliable. In certain embodiments, theself-diagnostics module counts the number of times a failure or reset isrequired (for example, how many times the system is forced intosuspended or start-up mode), wherein a count threshold is set for apredetermined time period, above which the system is considered to beunreliable. In certain embodiments, the self-diagnostics module comparesnewly received calibrated sensor data with previously calibrated sensordata for aberrant values, such as is described in more detail withreference to FIG. 5, above. In certain embodiments, the self-diagnosticsmodule evaluates clinical acceptability, such as is described in moredetail with reference to FIG. 18, above. In certain embodiments,diagnostics, such as are described in co-pending U.S. patent applicationSer. No. 11/007,635 filed Dec. 7, 2004 and U.S. patent application Ser.No. 11/004,561 filed Dec. 3, 2004, can be incorporated into the systemsof preferred embodiments for system diagnosis, for example, foridentifying interfering species on the sensor signal and for identifyingdrifts in baseline and sensitivity of the sensor signal.

At block 288, a mode determination module, which can be a part of thesensor evaluation module 224, determines in which mode the sensor shouldbe set (or remain). In some embodiments, the system is programmed withthree modes: 1) start-up mode; 2) normal mode; and 3) suspended mode.Although three modes are described herein, the preferred embodiments arelimited to the number or types of modes with which the system can beprogrammed. In some embodiments, the system is defined as “in-cal” (incalibration) in normal mode; otherwise, the system is defined as“out-of-cal” (out of calibration) in start-up and suspended mode. Theterms as used herein are meant to describe the functionality and are notlimiting in their definitions.

Preferably, a start-up mode is provided, wherein the start-up mode isset when the system determines that it can no longer remain in suspendedor normal mode (for example, due to problems detected by theself-diagnostics module, such as described in more detail above) and/orwherein the system is notified that a new sensor has been inserted. Uponinitialization of start-up mode, the system ensures that any old matcheddata pairs and/or calibration information is purged. In start-up mode,the system initializes the calibration set, such as described in moredetail with reference to FIG. 13, above. Once the calibration set hasbeen initialized, sensor data is ready for conversion and the system isset to normal mode.

Preferably, a normal mode is provided, wherein the normal mode is setwhen the system is accurately and reliably converting sensor data, forexample, wherein clinical acceptability is positively determined,aberrant values are negatively determined, and/or the self-diagnosticsmodules confirms reliability of data. In normal mode, the systemcontinuously (or intermittently) converts (calibrates) sensor data.Additionally, reference analyte values received by the system arematched with sensor data points and added to the calibration set.

In certain embodiments, the calibration set is limited to apredetermined number of matched data pairs, after which the systemspurges old or less desirable matched data pairs when a new matched datapair is added to the calibration set. Less desirable matched data pairscan be determined by inclusion criteria, which include one or morecriteria that define a set of matched data pairs that form asubstantially optimal calibration set.

One inclusion criterion comprises ensuring the time stamp of the matcheddata pairs (that make up the calibration set) span at least apreselected time period (e.g., three hours). Another inclusion criterioncomprises ensuring that the time stamps of the matched data pairs arenot more than a preselected age (e.g., one week old). Another inclusioncriterion ensures that the matched pairs of the calibration set have asubstantially evenly distributed amount of high and low raw sensor datapoints, estimated sensor analyte values, and/or reference analytevalues. Another criterion comprises ensuring all raw sensor data,estimated sensor analyte values, and/or reference analyte values arewithin a predetermined range (e.g., 40 mg/dL to 400 mg/dL for glucosevalues). Another criterion comprises evaluating the rate of change ofthe analyte concentration (e.g., from sensor data) during the time stampof the matched pair(s). For example, sensor and reference data obtainedduring the time when the analyte concentration is undergoing a slow rateof change can be less susceptible to inaccuracies caused by time lag andother physiological and non-physiological effects. Another criterioncomprises evaluating the congruence of respective sensor and referencedata in each matched data pair; the matched pairs with the mostcongruence can be chosen. Another criterion comprises evaluatingphysiological changes (e.g., low oxygen due to a user's posture,position, or motion that can cause pressure on the sensor and effect thefunction of a subcutaneously implantable analyte sensor, or othereffects such as described with reference to FIG. 6) to ascertain alikelihood of error in the sensor value. Evaluation of calibration setcriteria can comprise evaluating one, some, or all of the abovedescribed inclusion criteria. It is contemplated that additionalembodiments can comprise additional inclusion criteria not explicitlydescribed herein.

Unfortunately, some circumstances can exist wherein a system in normalmode can be changed to start-up or suspended mode. In general, thesystem is programmed to change to suspended mode when a failure ofclinical acceptability, aberrant value check and/or otherself-diagnostic evaluation is determined, such as described in moredetail above, and wherein the system requires further processing todetermine whether a system re-start is required (e.g., start-up mode).In general, the system will change to start-up mode when the system isunable to resolve itself in suspended mode and/or when the systemdetects a new sensor has been inserted (e.g., via system trigger or userinput).

Preferably, a suspended mode is provided wherein the suspended mode isset when a failure of clinical acceptability, aberrant value check,and/or other self-diagnostic evaluation determines unreliability ofsensor data. In certain embodiments, the system enters suspended modewhen a predetermined time period passes without receiving a referenceanalyte value. In suspended mode, the calibration set is not updatedwith new matched data pairs, and sensor data can optionally beconverted, but not displayed on the user interface. The system can bechanged to normal mode upon resolution of a problem (positive evaluationof sensor reliability from the self-diagnostics module, for example).The system can be changed to start-up mode when the system is unable toresolve itself in suspended mode and/or when the system detects a newsensor has been inserted (via system trigger or user input).

The systems of preferred embodiments, including a transcutaneous analytesensor, mounting unit, electronics unit, applicator, and receiver forinserting the sensor, and measuring, processing, and displaying sensordata, provide improved convenience and accuracy because of theirdesigned stability within the host's tissue with minimum invasivetrauma, while providing a discreet and reliable data processing anddisplay, thereby increasing overall host comfort, confidence, safety,and convenience. Namely, the geometric configuration, sizing, andmaterial of the sensor of the preferred embodiments enable themanufacture and use of an atraumatic device for continuous measurementof analytes, in contrast to conventional continuous glucose sensorsavailable to persons with diabetes, for example. Additionally, thesensor systems of preferred embodiments provide a comfortable andreliable system for inserting a sensor and measuring an analyte levelfor up to 7 days or more without surgery. The sensor systems of thepreferred embodiments are designed for host comfort, with chemical andmechanical stability that provides measurement accuracy. Furthermore,the mounting unit is designed with a miniaturized and reusableelectronics unit that maintains a low profile during use. The usablelife of the sensor can be extended by incorporation of a bioactive agentinto the sensor that provides local release of an anti-inflammatory, forexample, in order to slow the subcutaneous foreign body response to thesensor.

After the usable life of the sensor (for example, due to a predeterminedexpiration, potential infection, or level of inflammation), the host canremove the sensor and mounting from the skin, and dispose of the sensorand mounting unit (preferably saving the electronics unit for reuse).Another sensor system can be inserted with the reusable electronics unitand thus provide continuous sensor output for long periods of time.

Wholly Implantable Analyte Sensor

While aspects of the above described preferred embodiments are directedprimarily to a transcutaneous glucose sensor, the components and methodscan be used as is, or adapted and modified to be suitable for use in awholly implantable analyte sensor. FIG. 20 is an exploded perspectiveview of a sensor in an alternative embodiment including a whollyimplantable analyte sensor 10. Preferably, the sensor is whollyimplanted into the subcutaneous tissue of a host and includes systemsand methods such as are described in co-pending patent application Ser.No. 10/885,476 filed Jul. 6, 2004 and entitled “SYSTEMS AND METHODS FORMANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM”;co-pending U.S. patent application Ser. No. 10/838,912 filed May 3, 2004and entitled, “IMPLANTABLE ANALYTE SENSOR”; U.S. patent application Ser.No. 10/789,359 filed Feb. 26, 2004 and entitled, “INTEGRATED DELIVERYDEVICE FOR A CONTINUOUS GLUCOSE SENSOR”; U.S. application Ser. No.10/646,333 filed Aug. 22, 2003 entitled, “OPTIMIZED SENSOR GEOMETRY FORAN IMPLANTABLE GLUCOSE SENSOR”; U.S. application Ser. No. 10/633,367filed Aug. 1, 2003 entitled, “SYSTEM AND METHODS FOR PROCESSING ANALYTESENSOR DATA”; and U.S. Pat. No. 6,001,067 issued Dec. 14, 1999 andentitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS.”. The whollyimplantable sensor is configured for long sensor life, e.g., forimplantation in a host for at least about a few weeks, more preferablyat least about a month, even more preferably at least about a fewmonths, even more preferably at least about six month, and even morepreferably at least about a year or more.

In one exemplary embodiment, the analyte sensor comprises a glucosesensor that utilizes amperometric electrochemical sensor technology tomeasure glucose. FIG. 20 illustrates a wholly implantable glucose sensorcomprising a body 12 with a sensing region 14 including an electrodesystem 16 a and sensor electronics, which are configured as described inmore detail with reference to FIG. 13 above. The body 12 of the devicecan be formed from a variety of materials, including metals, ceramics,plastics, or composites thereof. In one embodiment, the device is formedfrom a thermoset polymer molded around the device electronics.Co-pending U.S. patent application Ser. No. 10/646,333, filed Aug. 22,2003 and entitled “OPTIMIZED DEVICE GEOMETRY FOR AN IMPLANTABLE GLUCOSEDEVICE” discloses suitable configurations for the sensor body, and isincorporated by reference in its entirety.

In this embodiment, the electrode system 16 a is operably connected tosensor electronics and includes electroactive surfaces, which aredescribed in more detail in co-pending U.S. patent application Ser. No.10/828,909, filed May 3, 2004, and entitled “IMPLANTABLE ANALYTESENSOR,” which is incorporated herein by reference in its entirety. Inone example, the electrode system extends through the material thatforms implantable body and is operably connected to the RF circuitryencased therein. The electroactive surfaces of the electrodes arecovered by a membrane system 18. The membrane system can be attached tothe sensor body 12 by mechanical or chemical methods such as aredescribed in co-pending U.S. patent application Ser. No. 10/885,476filed Jul. 6, 2004, and entitled “SYSTEMS AND METHODS FOR MANUFACTURE OFAN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM”, and U.S.patent application Ser. No. 10/838,912 filed May 3, 2004, and entitled“IMPLANTABLE ANALYTE SENSOR.”

In some embodiments, the electrode system 16 a, which is located on orwithin the sensing region 14, is comprised of at least a working and areference electrode with an insulating material disposed therebetween.In some alternative embodiments, additional electrodes can be includedwithin the electrode system, for example, a three-electrode system(working, reference, and counter electrodes) and/or an additionalworking electrode (which can be used to generate oxygen, measure anadditional analyte, or can be configured as a baseline subtractingelectrode, for example).

In some embodiments, the working electrode has a diameter of from about0.005 inches or less to about 0.100 inches or more, preferably fromabout 0.010 inches to about 0.040 inches, and more preferably about0.020 inches. Accordingly, the exposed surface area of the workingelectrode is preferably from about 0.00002 in² or less to about 0.0079in² or more (assuming a diameter of from about 0.005 inches to about0.100 inches), and more preferably about 0.0003 in². The preferredexposed surface area of the working electrode is selected to produce ananalyte signal with a current in the picoAmp range, such as is describedin more detail elsewhere herein. However, achieving a current in thepicoAmp range can be dependent upon a variety of factors, for example,including the electronic circuitry design (e.g., sample rate, currentdraw, A/D converter bit resolution, and the like), the membrane system(e.g., permeability of the analyte through the membrane system), and theexposed surface area of the working electrode. Accordingly, the exposedelectroactive working electrode surface area can be selected to have avalue greater than or less than the above-described ranges taking intoconsideration alterations in the membrane system and/or electroniccircuitry. In preferred embodiments of a glucose sensor, it can beadvantageous to minimize the surface area of the working electrode whilemaximizing the diffusivity of glucose in order to optimize thesignal-to-noise ratio while maintaining sensor performance in both highand low glucose concentration ranges.

In the embodiment of the sensor illustrated in FIG. 20, the electrodesystem includes three electrodes (working, counter, and referenceelectrodes), wherein the counter electrode is provided to balance thecurrent generated by the species being measured at the workingelectrode. In a glucose oxidase based glucose sensor, the speciesmeasured at the working electrode is H₂O₂. The change in H₂O₂ can bemonitored to determine glucose concentration. As noted above, the H₂O₂produced from the glucose oxidase reaction further reacts at the surfaceof working electrode and produces two protons (2H+), two electrons(2e−), and one oxygen molecule (O₂). In such embodiments, because thecounter electrode utilizes oxygen as an electron acceptor, the mostlikely reducible species for this system is oxygen or enzyme generatedperoxide.

There are two main pathways by which oxygen can be consumed at thecounter electrode. These pathways include a four-electron pathway toproduce hydroxide and a two-electron pathway to produce hydrogenperoxide. In addition to the counter electrode, oxygen is furtherconsumed by the reduced glucose oxidase within the enzyme layer.Therefore, due to the oxygen consumption by both the enzyme and thecounter electrode, there is a net consumption of oxygen within theelectrode system. Theoretically, in the domain of the working electrodethere is significantly less net loss of oxygen than in the region of thecounter electrode. In some electrochemical cell configurations, there isa close correlation between the ability of the counter electrode tomaintain current balance and sensor function. In some sensorconfigurations, it is believed that that counter electrode functionbecomes limited before the enzyme reaction becomes limited when oxygenconcentration is lowered.

In general, in electrochemical sensors wherein an enzymatic reactiondepends on oxygen as a co-reactant, depressed function or inaccuracy canbe experienced in low oxygen environments, for example, in vivo.Subcutaneously implanted sensors are especially susceptible to transientischemia that can compromise sensor function. For example, because ofthe enzymatic reaction required for an implantable amperometric glucosesensor, oxygen must be in excess over glucose at the sensor in order forit to effectively function as a glucose sensor. If glucose becomes inexcess, the sensor turns into an oxygen sensitive device.

In vivo, glucose concentration can vary from about one hundred times ormore than that of the oxygen concentration. Consequently, oxygen becomesa limiting reactant in the electrochemical reaction and wheninsufficient oxygen is provided to the sensor, the sensor is unable toaccurately measure glucose concentration. Those skilled in the artinterpret oxygen limitations resulting in depressed function orinaccuracy as a problem of availability of oxygen to the enzyme. Oxygenlimitations can also be seen during periods of transient ischemia thatoccur, for example, under certain postures or when the region around theimplanted sensor is compressed so that blood is forced out of thecapillaries. Such ischemic periods observed in implanted sensors canlast for many minutes or even an hour or longer.

Consequently, one limitation of conventional enzymatic analyte sensorscan be caused by oxygen deficiencies. When oxygen is deficient relativeto the amount of glucose (in the example of an enzymatic glucosesensor), then the enzymatic reaction is limited by oxygen rather thanglucose. Thus, the output signal is indicative of the oxygenconcentration rather than the glucose concentration, producing erroneoussignals.

The wholly-implantable glucose sensors of preferred embodimentstypically consume 5 μg or less of enzyme over their operationallifetimes (typically 2 years or more).

Sensor Electronics for Wholly Implantable Sensor

In general, sensor electronics for a wholly implantable sensor areconfigured substantially as described with reference to FIG. 13, above.In some embodiments, the potentiostat includes a resistor (not shown)that translates the current into voltage. In some alternativeembodiments, a current to frequency converter is provided that isconfigured to continuously integrate the measured current, for example,using a charge counting device.

As described in detail above with reference to the transcutaneousanalyte sensor embodiment, the wholly implantable sensor is similarlyconfigured to measure the current flow in the picoAmp range, and in someembodiments, femtoAmps. Namely, for every unit (mg/dL) of glucosemeasured, at least one picoAmp of current is measured. Preferably, theanalog portion of the A/D converter is configured to continuouslymeasure the current flowing at the working electrode and to convert thecurrent measurement to digital values representative of the current. Inone embodiment, the current flow is measured by a charge counting device(e.g., a capacitor). Thus, a signal is provided, whereby a highsensitivity maximizes the signal received by a minimal amount ofmeasured hydrogen peroxide (e.g., minimal glucose requirements withoutsacrificing accuracy even in low glucose ranges), reducing thesensitivity to oxygen limitations in vivo (e.g., in oxygen-dependentglucose sensors).

Electrode System for Wholly Implantable Sensor

A three-electrode system is generally preferred for use in a whollyimplantable sensor. Reference is made to FIG. 21, which is a circuitdiagram of a potentiostat 20 configured to control the three-electrodesystem 16 a described above. The potentiostat 20 is employed to monitorthe electrochemical reaction at the electroactive surface(s) by applyinga constant potential to the working and reference electrodes todetermine a current value. The current that is produced at the workingelectrode (and flows through the circuitry to the counter electrode) issubstantially proportional to the amount of H₂O₂ that diffuses to theworking electrode. Accordingly, a raw signal can be produced that isrepresentative of the concentration of glucose in the user's body, andtherefore can be utilized to estimate a meaningful glucose value.

In one embodiment, the potentiostat includes electrical connections tothe working electrode 32, the reference electrode 34, and the counterelectrode 36. The voltage applied to the working electrode 32 is aconstant value and the voltage applied to the reference electrode isalso set at a constant value such that the potential (V_(BIAS)) appliedbetween the working and reference electrodes is maintained at a constantvalue. The counter electrode 36 is configured to have a constant current(equal to the current being measured by the working electrode 32), whichis accomplished by varying the voltage at the counter electrode in orderto balance the current going through the working electrode 32 such thatcurrent does not pass through the reference electrode 34. A negativefeedback loop 38 is constructed from an operational amplifier (OP AMP),the reference electrode 34, the counter electrode 36, and a referencepotential (V_(REF)), to maintain the reference electrode at a constantvoltage.

As described in more detail above, many electrochemical sensors face achallenge in maintaining sensor output during ischemic conditions, whichcan occur, for example, either as short-term transient events in vivo(for example, compression caused by postural effects on the device) oras long-term low oxygen conditions in vivo (for example, caused by athickened FBC or by barrier cells). When the sensor is in a low oxygenenvironment, the potentiostat reacts by decreasing the voltage relativeto the reference electrode voltage applied to the counter electrode,which can result in other less electroactive species reacting at thecounter electrode.

Accordingly, the preferred embodiments involve setting the bias(V_(BIAS)), also referred to as the applied potential (for example,voltage difference between working and reference electrodes), of thesensor to a level where a continuous background level of oxygen isproduced in reactions with water or other electroactive species, whichis in contrast to conventional electrochemical systems that typicallyset their bias at a level such that the sensing (working) electrodemeasures a signal only from the product of the enzyme reaction. In theexample of a glucose sensor such as described above, a bias setting ofabout +0.6 V has conventionally been used to successfully oxidize andmeasure H₂O₂ without oxidizing and measuring water or otherelectroactive species (See, e.g., U.S. Pat. No. 5,411,647 to Johnson, etal.)

However, the methods of preferred embodiments typically employ anincreased bias potential setting in an electrode system such that theworking electrode not only successfully oxidizes and measures H₂O₂ butalso additionally oxidizes and measures water or other electroactivespecies. In one example, the bias setting can be increased by about 0.05V to about 0.4 V above what is necessary for sufficient H₂O₂measurements, for example. The products of the water electrolysisreaction (and some other electroactive species) are oxygen at theworking electrode and hydrogen at the counter electrode. The oxygenproduced at the working electrode diffuses in all directions includingup to the glucose oxidase directly above the working electrode and alsoover to the surface of the counter electrode. This production of oxygenat the working electrode allows increased sensor function even in lowoxygen environments.

An increased bias potential, which results in increased oxidation, alsoincreases the current measured by the working electrode. While notwishing to be bound by any particular theory, it is believed that theincreased bias potential is substantially linear and measurable;therefore, the increased bias potential will not affect themeasurability of the analyte of interest (for example, glucose).

In some embodiments, the bias is continuously set at a desired bias, forexample, between about +0.65 and about +1.2 Volts, in order tocontinuously oxidize and/or measure water or other electroactivespecies. The potentiostat can be configured to incrementally switchbetween a plurality of different bias settings, for example the bias canbe switched between a first bias setting and a second bias setting atregular intervals or during break-in or system start-up. For example,the first bias setting (for example, +0.6V) can measure a signal onlyfrom the product of the enzyme reaction, however at certainpredetermined times (for example, during a system break-in period ofbetween about 1 hour and 3 days), the potentiostat can be configured toswitch to the second bias setting (for example, +1.0V) that oxidizes andmeasures water or other electroactive species.

Alternatively, the potentiostat can be configured to selectively orvariably switch between two or more bias settings based on a variety ofconditions, such as oxygen concentration, signal noise, signalsensitivity, baseline shifts, or the like. For example, a first biassetting (for example, +0.6V) can measure a signal only from the productof the enzyme reaction, however, when oxygen limitations are detected,the system can be configured to switch to a second bias setting (forexample, +0.8V) to oxidize water or other electroactive species in orderto generate usable oxygen.

In certain embodiments, pulsed amperometric detection is employed toincrementally and/or cyclically switch between a plurality of differentbias settings. For example, the controller can be configured to hold anoptimized oxygen-generating potential (for example, +1.0V) except duringanalyte measurements, during which the controller is configured toswitch to an optimized analyte-sensing potential (for example, +0.6V)for a time period sufficient to measure the analyte. An appropriate“break-in” time period and/or a temporarily lower potential (+0.4V) canbe implemented to ensure accurate analyte measurements are obtained, asis appreciated by one skilled in the art. A variety of systems andmethods can be used for detecting oxygen limitations, such as signalartifact detection, oxygen monitoring, signal sensitivity, baselineshifts, or the like, which are described in more detail below.

Membrane System for Wholly Implantable Sensor

The membrane system for a wholly implantable sensor (e.g., animplantable glucose sensor) can include two or more domains aspreviously described. For implantable enzyme-based electrochemicalglucose sensors, the membrane prevents direct contact of the biologicalfluid sample with the electrodes, while controlling the permeability ofselected substances (for example, oxygen and glucose) present in thebiological fluid through the membrane for reaction in an enzyme richdomain with subsequent electrochemical reaction of formed products atthe electrodes.

The membrane systems of for use with wholly implantable sensors ofpreferred embodiments are typically constructed of two or more domains.The multi-domain membrane can be formed from one or more distinct layersand can comprise the same or different materials. The term “domain” is abroad term and is used in its ordinary sense, including, withoutlimitation, a single homogeneous layer or region that incorporates thecombined functions one or more domains, or a plurality of layers orregions that each provide one or more of the functions of each of thevarious domains.

FIG. 22 is an illustration of a membrane system in one preferredembodiment. The membrane system 18 can be used with a glucose sensorsuch as is described above with reference to FIG. 1. In this embodiment,the membrane system 18 includes a biointerface membrane comprising acell disruptive domain 40 most distal of all domains from theelectrochemically reactive surfaces and a cell impermeable domain 42less distal from the electrochemically reactive surfaces than the celldisruptive domain, and a sensing membrane comprising a resistance domain44 less distal from the electrochemically reactive surfaces than thecell impermeable domain, an enzyme domain 46 less distal from theelectrochemically reactive surfaces than the resistance domain, aninterference domain 48 less distal from the electrochemically reactivesurfaces than the enzyme domain, and an electrolyte domain 50 adjacentto the electrochemically reactive surfaces. However, it is understoodthat the membrane system can be modified for use in other devices, byincluding only two or more of the domains, or additional domains notrecited above.

In some embodiments, the membrane system is formed as a homogeneousmembrane, namely, a membrane having substantially uniformcharacteristics from one side of the membrane to the other. However, amembrane can have heterogeneous structural domains, for example, domainsresulting from the use of block copolymers (for example, polymers inwhich different blocks of identical monomer units alternate with eachother), but can be defined as homogeneous overall in that each of theabove-described domains functions by the preferential diffusion of somesubstance through the homogeneous membrane.

In some embodiments, the domains are serially cast upon a liner, all ofwhich are formed on a supporting platform; however alternativeembodiments may form the membrane domains directly on the sensingregion, for example, by spin-, spray-, or dip-coating.

Particularly preferred for use with wholly implantable sensors is abiointerface membrane comprising one or more domains disposed moredistal to the electroactive surface than the sensing membrane thatinteract with the host's tissue. Preferably, the biointerface membranesupports tissue ingrowth, serves to interfere with the formation of abarrier cell layer, and protects the sensitive regions of the devicefrom host inflammatory response. In some embodiments, the biointerfacemembrane is composed of one or more domains.

In a wholly implantable sensor of one embodiment as depicted in FIG. 23,the biointerface membrane generally includes a cell disruptive domain108 most distal from the electrochemically reactive surfaces and a cellimpermeable domain 110 less distal from the electrochemically reactivesurfaces than the cell disruptive domain 108. The cell disruptive domain108 comprises an architecture, including a cavity size, configuration,and overall thickness that encourages vascular tissue ingrowth anddisrupts barrier cell formation in vivo, and a cell impermeable domainthat comprises a cell impermeable layer that is resistant to cellularattachment and has a robust interface that inhibits attachment ofbarrier cells and delamination of the domains.

FIG. 22 is a cross-sectional schematic view of a biointerface membrane106 in vivo in one embodiment, wherein the biointerface membranecomprises a cell disruptive domain 108 and cell impermeable domain 110.The architecture of the biointerface membrane provides a robustlong-term implantable membrane that allows the transport of analytesthrough vascularized tissue ingrowth without the formation of a barriercell layer.

The cell disruptive domain 108 comprises a solid portion 112 and aplurality of interconnected three-dimensional cavities 114 formedtherein. The cavities 114 have sufficient size and structure to allowinvasive cells, such as fibroblasts 116, fibrous matrix 118, and bloodvessels 120 to completely enter into the apertures that define theentryway into each cavity 114, and to pass through the interconnectedcavities toward the interface 122 between the cell disruptive and cellimpermeable domains (cells and blood vessels are disproportionatelylarge in the illustration). The cavities 114 comprise an architecturethat encourages the ingrowth of vascular tissue in vivo as indicated bythe blood vessels 120 formed throughout the cavities. Because of thevascularization within the cavities, solutes 126 (for example, oxygen,glucose and other analytes) can pass through the first domain withrelative ease and/or the diffusion distance (i.e., distance that theglucose diffuses) can be reduced.

The cell impermeable domain 110 comprises a cell impermeable layer thatmay be resistant to cellular attachment and thus provides anothermechanism for resisting barrier cell layer formation (indicated in FIG.22 by few macrophages and/or giant cells at the interface 122 betweenthe domains). Because the cell impermeable domain 110 is resistant tocellular attachment and barrier cell layer formation, the transport ofsolutes such as described above can also pass through with relative easewithout blockage by barrier cells as seen in the prior art.

Reference is now made to FIG. 24, which is an illustration of themembrane of FIG. 23, showing contractile force lines 128 caused by thefibrous tissue (for example, from the fibroblasts and fibrous matrix) ofthe foreign body capsule (FBC). Particularly, the architecture of thecell disruptive domain 108, including the cavity interconnectivity andmultiple-cavity depth, (i.e., two or more cavities in three dimensionsthroughout a substantial portion of the first domain) can affect thetissue contracture that typically occurs around a foreign body.

A contraction of the FBC around the device as a whole produces downwardforces on the device, which can be helpful in reducing motion artifacts,such as is described with reference to co-pending U.S. patentapplication Ser. No. 10/646,333, filed Aug. 22, 2003, and entitled“OPTIMIZED SENSOR GEOMETRY FOR AN IMPLANTABLE GLUCOSE SENSOR,” which isincorporated herein in its entirety by reference. However, thearchitecture of the first domain described herein, including theinterconnected cavities and solid portion, are advantageous because thecontractile forces caused by the downward tissue contracture that canotherwise cause cells to flatten against the device and occlude thetransport of analytes, is instead translated to, disrupted by, and/orcounteracted by the forces 128 that contract around the solid portions112 (for example, throughout the interconnected cavities 114) away fromthe device. That is, the architecture of the solid portions 112 andcavities 114 of the cell disruptive domain cause contractile forces 128to disperse away from the interface between the cell disruptive domain108 and cell impermeable domain 110. Without the organized contractureof fibrous tissue toward the tissue-device interface typically found ina FBC, macrophages and foreign body giant cells substantially do notform a monolayer of cohesive cells (i.e., barrier cell layer) andtherefore the transport of molecules across the second domain and/ormembrane is substantially not blocked (indicated by free transport ofanalytes 128 through the domains in FIG. 23).

Co-pending U.S. Pat. No. 6,702,857; U.S. Publication No. 2005-0112169-A1and U.S. patent application Ser. No. 11/055,779, filed Feb. 9, 2005, andentitled “BIOINTERFACE WITH MACRO- AND MICRO-ARCHITECTURE” describebiointerface membranes that can be used in conjunction with thepreferred embodiments.

The cell disruptive and cell impermeable domains can be formed frommaterials such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable, homopolymers, copolymers, terpolymers ofpolyurethanes, polypropylene (PP), polyvinylchloride (PVC), polyvinylalcohol (PVA), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones or blockcopolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers.

The cell disruptive domain and cell impermeable domain of thebiocompatible membrane can be formed together as one unitary structure.Alternatively, the cell disruptive and cell impermeable domains of thebiocompatible membrane can be formed as two layers mechanically orchemically bonded together. In yet another embodiment, the cellimpermeable domain is chemically or mechanically attached to the sensingmembrane. In some embodiments, the bioprotective function of the cellimpermeable domain is inherent in the structure of the sensing membraneand therefore no discrete cell impermeable domain is required.

In preferred embodiments of wholly implantable sensors, the sensingmembrane is the same as or similar to the membrane system describedabove in connection with a transcutaneous sensor of a preferredembodiment. For example, the sensing membrane can be constructed of twoor more domains and is disposed adjacent to the electroactive surfacesof the sensing region. The sensing membrane provides functional domainsthat enable measurement of the analyte at the electroactive surfaces.For example, the sensing membrane can include an enzyme (e.g., an enzymedomain), which catalyzes the reaction of the analyte being measured witha co-reactant (for example, glucose and oxygen) in order to produce aspecies that in turn generates a current value at the working electrode,such as described in more detail above. The enzyme can be, for example,glucose oxidase, and covers the electrolyte phase. In one embodiment,the sensing membrane generally includes a resistance domain most distalfrom the electrochemically reactive surfaces, an enzyme domain lessdistal from the electrochemically reactive surfaces than the resistancedomain, and an electrolyte domain adjacent to the electrochemicallyreactive surfaces, such as is described above. However, it is understoodthat a sensing membrane modified for other devices, for example, byincluding fewer or additional domains, is within the scope of thepreferred embodiments. The sensing membrane can be formed from one ormore distinct layers and can comprise the same or different materials.Co-pending U.S. Patent Publ. No. 2003-0032874 A1 and U.S. Patent Publ.No. 2003-0217966 A1 describe membranes that can be used in the preferredembodiments. It is noted that in some embodiments, the sensing membranemay additionally include an interference domain that limits someinterfering species; such as described elsewhere herein and in moredetail in the above-cited co-pending patent application. Co-pending U.S.Patent Publ. No. 2005-0090607 A1 also describes membranes that may beused for the sensing membrane of the preferred embodiments.

In general, the membrane system provides one or more of the followingfunctions: 1) protection of the exposed electrode surface from thebiological environment; 2) diffusion resistance (limitation) of theanalyte; 3) a catalyst for enabling an enzymatic reaction; 4) limitationor blocking of interfering species; and 5) hydrophilicity at theelectrochemically reactive surfaces of the sensor interface, forexample, such as is described in co-pending U.S. Patent Publ. No.2005-0245799 A1.

In some embodiments, the domains of the sensing membrane are formed frommaterials such as the porous biointerface materials listed above,including silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene,polyvinylchloride, polyvinylidene difluoride, polybutyleneterephthalate, polymethylmethacrylate, polyether ether ketone,polyurethanes, cellulosic polymers, polysulfones and block copolymersthereof.

Each of the domains of the sensing membrane is described in more detailwith reference to FIG. 5C above. However, it is particularly noted thatthe resistance domain of the sensor of these alternative embodiments isconfigured in a substantially similar manner such as described in moredetail with reference to FIG. 5C above; namely, configured to provide asensor signal with a current in the picoAmp range. In addition to theadvantages described elsewhere herein, the resistance domain (e.g.,permeability of the analyte through the resistance domain), incombination the electronic circuitry design (e.g., A/D converter, bitresolution, and the like), enzyme concentration, electrolyteavailability to the electrochemical reaction at the electrodes), and/orthe exposed surface area of the working electrode are particularlyadvantageous in enabling implantation within the subcutaneous tissuelong-term (e.g., a few weeks to a year or more), even when oxygen has isknown to be limiting due to in vivo factors, which are described in moredetail below.

Oxygen limitations may occur in vivo, for example, ischemia within oraround a glucose sensor, for at least a couple of reasons. As a firstexample in a glucose sensor, at high glucose levels, oxygen can becomelimiting to the enzymatic reaction, resulting in a non-glucose dependentdownward trend in the data, such as described in more detail inco-pending U.S. Published Patent Application No. US 2005-0043598. As asecond example, certain movements or postures taken by the patient cancause transient downward noise as blood is squeezed out of thecapillaries resulting in local ischemia, and causing non-glucosedependent low noise. Because excess oxygen (relative to glucose) isnecessary for proper sensor function, transient ischemia can result in aloss of signal gain in the sensor data. In this second example oxygencan also become transiently limited due to contracture of tissues aroundthe sensor interface. This is similar to the blanching of skin that canbe observed when one puts pressure on it. Under such pressure, transientischemia can occur in both the epidermis and subcutaneous tissue.Transient ischemia is common and well tolerated by subcutaneous tissue.

Accordingly, in preferred embodiments, the membrane system for use inwholly implantable sensors is designed with the same or a similarsensitivity as that of the membrane for use with transcutaneous sensorsas described above, namely, a sensitivity of from about 1 pA/mg/dL toabout 100 pA/mg/dL, preferably from about 5 pA/mg/dL to 25 pA/mg/dL, andmore preferably from about 3.5 to about 7.5 pA/mg/dL.

Example 1

FIG. 25A is a graphical representation showing transcutaneous glucosesensor data and corresponding blood glucose values over time in a human.The x-axis represents time, the first y-axis represents current inpicoAmps, and the second y-axis represents blood glucose in mg/dL. Asdepicted on the legend, the small diamond points represent the currentmeasured from the working electrode of a transcutaneous glucose sensorof a preferred embodiment; while the larger points represent bloodglucose values of blood withdrawn from a finger stick and analyzed usingan in vitro self-monitoring blood glucose meter (SMBG).

A transcutaneous glucose sensor was constructed according to thepreferred embodiments and implanted in a human host where it remainedover a period of time. The graph illustrates approximately 3 days ofdata obtained by the electronics unit operably connected to the sensorimplanted in the human host. Finger-prick blood samples were takenperiodically and glucose concentration measured by a blood glucose meter(SMBG). The graph shows the subcutaneous sensor data obtained by thetranscutaneous glucose sensor tracking glucose concentration as it risesand falls over time. The time-corresponding blood glucose values showthe correlation of the sensor data to the blood glucose data, indicatingappropriate tracking of glucose concentration over time.

The signal has a current measurement in the picoAmp range. Namely, forevery unit (mg/dL) of glucose, approximately 3.5 to 7.5 pA of current ismeasured. Generally, the approximately 3.5 to 7.5 pA/mg/dL sensitivityexhibited by the device can be attributed to a variety of designfactors, including resistance of the membrane system to glucose, surfacearea of the working electrode, and electronic circuitry design.Advantageously, the transcutaneous analyte sensors of the preferredembodiments exhibit improved performance over convention analyte sensorsat least in part because a current in the picoAmp range enables lessenzyme, less oxygen, better resolution, lower power usage, and thereforebetter performance in the hypoglycemic range wherein lower mg/dL valuesconventionally have yielded lower accuracy.

FIG. 25B is a graphical representation showing transcutaneous glucosesensor data and corresponding blood glucose values over time in a human.The x-axis represents time; the y-axis represents glucose concentrationin mg/dL. As depicted on the legend, the small diamond points representthe calibrated glucose data measured from a transcutaneous glucosesensor of a preferred embodiment; while the larger points representblood glucose values of blood withdrawn from a finger stick and analyzedusing an in vitro self-monitoring blood glucose meter (SMBG). Thecalibrated glucose data corresponds to the data of FIG. 25A shown incurrent, except it has been calibrated using algorithms of the preferredembodiments. Accordingly, accurate subcutaneous measurement of glucoseconcentration has been measured and processed using the systems andmethods of the preferred embodiments.

Example 2

A wholly implantable glucose sensor generally as described above wasconstructed as is described in more detail with reference to U.S. Pat.No. 6,001,067. A sensing membrane was constructed comprisingpolyurethanes. The polyurethanes were prepared as block copolymers bysolution polymerization techniques as generally described in Lyman [J.Polymer Sci. 45:49 (1960)]. Specifically, a two-step solutionpolymerization technique was used in which the poly(oxyethylene) glycolwas first “capped” by reaction with a diisocyanate to form amacrodiisocyanate. The macrodiisocyanate was then coupled with a diol(or diamine) and the diisocyanate to form a block copolyetherurethane(or a block copolyurethaneurea). The resulting block copolymers weretough and elastic and could be solution-cast in N,N-dimethylformamide toyield clear films that demonstrated good wet strength when swollen inwater.

A mixture of 8.4 g (0.006 mol), poly(oxyethylene) glycol (CARBOWAX®1540, Union Carbide), and 3.0 g (0.012 mol) 4,4′-diphenylmethanediisocyanate in 20 mL dimethyl sulfoxide/4-methyl-2-pentanone (50/50)was placed in a three-necked flask equipped with a stirrer and condenserand protected from moisture. The reaction mixture was stirred and heatedat 110° C. for about one hour. To this clear solution was added 1.5 g(0.014 mol) 1,5-pentanediol and 2.0 g (0.008 mol) 4,4′-diphenylmethanediisocyanate.

After heating at 110° C. for an additional two hours, the resultingviscous solution was poured into water. The tough, rubbery, whitepolymer precipitate that formed was chopped in a Waring Blender, washedwith water and dried in a vacuum oven at about 60° C. The yield wasessentially quantitative. The inherent viscosity of the copolymer inN,N-dimethyl formamide was 0.59 at 30° C. (at a concentration of about0.05 percent by weight).

The electrolyte layer (typically, the membrane layer closest to theelectrode) can be coated as a water-swellable film. A coating comprisinga polyurethane having anionic carboxylate functional groups andhydrophilic polyether groups and polyvinylpyrrolidone (PVP) that can becross-linked by carbodiimide can be employed for preparing theelectrolyte layer.

A coating preparation is prepared comprising a premix of a colloidalaqueous dispersion of particles of a urethane polymer having apolycarbonate-polyurethane (PC-PU) backbone containing carboxylategroups and the water-soluble hydrophilic polymer, polyvinyl pyrrolidone(PVP), which is crosslinked by the addition of the cross-linking agentjust before production of the coated membrane.

The viscosity and pH of the premix can be controlled and maintainedduring processing and to prolong its useful life by adding water oradjusting the pH with dilute ammonia solution or an equivalent baseprior to adding the crosslinker.

For production, the coating is applied with a Mayer rod onto the unboundsurface of a multilayered membrane. The amount of coating applied shouldcast a film having a “dry film” thickness of about 2.5 μm to about 12.5μm, preferably about 6.0 μm. The coating is dried above room temperaturepreferably at about 50° C. This coating dries to a substantially solidgel-like film that is water swellable to maintain electrolyte betweenthe membrane covering the electrode and the electrode in the electrodeassembly during use.

The following procedure was used to determine the amount of enzyme to beincluded in the enzyme layer. It is to be understood that the preferredembodiments not limited to the use of this or a similar procedure, butrather use of other techniques known in the art can be employed.

A starting glucose oxidase concentration of 2×10⁻⁴ M was calculated fromthe enzyme weight and the final volume of an enzyme layer prepared asdescribed above. Thereafter, a series of eight additional membraneformulations was prepared by decrementing enzyme concentration in 50%steps (referred to as a change of one “half loading”) down to 7.8×10⁻⁷M. Sensor responses were then collected for this range of enzymeloadings and compared to computer-simulated sensor outputs. Thesimulation parameter set used included previously-determined membranepermeabilities and the literature mechanisms and kinetics for glucoseoxidase. [Rhodes et al., Anal. Chem., 66:1520-1529 (1994)].

There was a good match of real-to-simulated sensor output at allloadings (data not shown). Approximately a six-to-seven “half loading”drop in enzyme activity was required before the sensor output dropped10%; another two-to-three half loading drop in enzyme activity wasrequired to drop the sensor response to 50% of the fully loaded sensorresponse. These results indicate that, at the loading used and the decayrates measured, up to two years of performance is possible from thesesensors when the sensor does not see extended periods of high glucoseand physiologically low O₂ concentrations.

A long-term glucose sensor device was subcutaneously implanted into adog and the biological response following implantation was monitored.The stages of FBC development are indicated by the long term glucosesensor device response. FIG. 26A graphically depicts glucose levels as afunction of the number of days post-implant. The data in FIG. 26A wastaken at four-minute intervals for 60 days after implantation. Sensorresponse is calculated from a single preimplant calibration at 37° C.Normal canine fasting glucose concentration of 5.5 mM is shown forcomparison.

The data set forth in FIG. 26A illustrates the four typicallyidentifiable phases in FBC formation. Phase 1 shows rapidly droppingresponse from the time of implant to, in this case, day 3. Though anunderstanding of the mechanism for this drop in sensor output is notrequired in order to practice the present invention, it is believed toreflect low pO₂ and low glucose present in fluid contacting the sensor.Phase 2 shows intermittent sensor-tissue contact in seroma fluid from,in this case, day 3 to about day 13. During this phase, fragile newtissue and blood supply intermittently make contact with the sensor(which is surrounded by seroma fluid). Phase 3 shows stabilization ofcapillary supply between, in this case, days 13 and 22. Morespecifically, the noise disappears and sensor output rises overapproximately six days to a long term level associated with tracking ofFBC glucose. Again, though an understanding of this effect is notrequired to practice the present invention, the effect is believed toreflect consistent contact of FBC tissue with the sensor surface. Phase4 from, in this case, day 22 to day 60, shows duration of useful sensordevice life. While there are timing variations of the stages from sensordevice to sensor device, generally speaking, the first three steps ofthis process take from 3 days to three weeks and continuous sensing hasbeen observed for periods thereafter (e.g., for periods of 150 days andbeyond).

In addition to collecting normoglycemic or non-diabetic dog data from asensor as shown in Example 4 of U.S. Pat. No. 6,001,067, calibrationstability, dynamic range, freedom from oxygen dependence, response timeand linearity of the sensor can be studied by artificial manipulation ofthe intravenous glucose of the host.

This was done via infusion of a 15 g bolus of 50% sterile Dextrose givenintravenously in less than about 20 seconds. Reference blood glucosedata was then taken from a different vein at 2-5 minute intervals for upto 2 hours after bolus infusion. FIG. 26B depicts correlation plots ofsix bolus infusion studies, at intervals of 7-10 days on one sensor of apreferred embodiment. Sensor glucose concentrations were calculatedusing a single 37° C. in vitro preimplantation calibration. The sensorresponse time was accounted for in calculating the sensor glucoseconcentrations at times of reference blood sampling by time shifting thesensor data 4 minutes.

As with any analytical system, periodic calibration is preferablyperformed. Thus, the methods of preferred embodiments preferably employsome interval of calibration and/or control testing to meet analytical,clinical, and/or regulatory requirements.

Further experiments were performed on glucose sensors manufactured asdescribed above, wherein the experiments were directed at sensoraccuracy and long-term glucose sensor response of several sensor devicesof preferred embodiments.

Pre-Implant In Vitro Evaluation

In vitro testing of the sensor devices was accomplished in a mannersimilar to that previously described. [Gilligan et al., Diabetes Care17:882-887 (1994)]. Briefly, sensor performance was verified bydemonstrating linearity to 100 mg/dL glucose concentration steps from 0mg/dL through 400 mg/dL (22 mM) with a 90% time response to the glucosesteps of less than 5 minutes. A typical satisfactory response to thisprotocol is shown in FIG. 27. Modulating dissolved oxygen concentrationfrom a pO₂ of 150 down to 30 mm Hg (0.25 to 0.05 mM) showed no more thana 10% drop in sensor output at 400 mg/dL for the preferred sensordevices. Stability of calibration was maintained within 10% for one weekbefore the final bioprotective and angiogenesis membranes were added tofinalize the implant package. A final calibration check was made and waswithin 20% of the prior results for the sensor to be passed on to theimplant stage. These final calibration factors (linear least squaresregression for the zero glucose current and output to 100 mg/dL current)were used for the initial in vivo calibration. Sensor devices were thenwet sterilized with 0.05% thimerosal for 24 hours just prior toimplantation.

The signal as shown in FIG. 27 has a current measurement in the picoAmprange. Namely, for every unit (mg/dL) of glucose, approximately 5.0 toabout 10.0 pA of current is measured, and more preferably 7.5 pA ofcurrent is measured, as extrapolated from the graph of FIG. 27.

In some embodiments, a sensitivity of from about 5 to about 25 pA/mg/dLis chosen, which can be modulated by a variety of design factors,including resistance of the membrane system to glucose (e.g., from atleast about 50/1 glucose-to-oxygen or less to about 200/1glucose-to-oxygen or more, preferably from about 100/1 glucose-to-oxygento about 200/1 glucose-to-oxygen, and more preferably from about 150/1glucose-to-oxygen to about 200/1 glucose-to-oxygen, surface area of theworking electrode (e.g., preferably 0.508 mm+/−0.025 mm; however higheror lower surface areas can be desirable, with adjustment of otherparameters, as appropriate), and electronic circuitry design.Accordingly, a current in the picoAmp range enables an analyte sensorthat: 1) requires (or utilizes) less enzyme (e.g., because the membranesystem is highly resistive and allows less glucose through for reactionin the enzyme domain); 2) requires less oxygen (e.g., because lessreaction of glucose in the enzyme domain requires less oxygen as aco-reactant) and therefore performs better during transient ischemia ofthe subcutaneous tissue and long-term reduction of oxygen that may occurin vivo; and 3) accurately measures glucose even in hypoglycemic ranges(e.g., because the electronic circuitry is able to measure very smallamounts of glucose (hydrogen peroxide at the working electrode)).

As in the transcutaneous systems described above, the wholly implantableanalyte sensors of the preferred embodiments advantageously exhibitimproved performance over conventional analyte sensors at least in partbecause of the benefits associated with currents in the picoAmp range,as also discussed above. Specifically, picoAmp range currents enablesless enzyme to be employed (e.g., 25 μg or less, preferably 5 μg or lessfor the life of the wholly implantable sensor), less oxygen to beconsumed (e.g., 2 μg of oxygen per year or less, depending upon theglucose-to-oxygen ratio of the resistance layer), overall betterresolution of individual glucose values, lower power usage, andtherefore better performance, particularly in the hypoglycemic range(e.g., below about 70 mg/dL, 60 mg/dL, 50 mg/dL, and/or 40 mg/dL)wherein lower mg/dL values conventionally have yielded lower accuracy.The power consumption of the wholly implantable sensors, as reflected inthe quiescent current, is also advantageously low. Quiescent current istypically less than about 0.3 mAh per day and preferably less than about0.03 mAh per day. Quiescent currents over a range of from about 0.003mAh per day or less to about 0.02, 0.03, 0.04, 0.05, 0.1, 0.15, 0.2, or0.3 mAh per day are generally preferred.

Additional experiments were performed and are described in U.S. Pat. No.6,001,067.

Example 3

A transcutaneous glucose sensor was constructed according to anembodiment described above and implanted in a human host where itremained over a period of time. The graph of FIG. 28A illustratesapproximately 1 week of data obtained by the electronics unit operablyconnected to the sensor transcutaneously inserted in the human host.Finger-prick blood samples were taken periodically and glucoseconcentration measured by a blood glucose meter. The graph shows thetranscutaneous sensor data obtained by the glucose sensor trackingglucose concentration as it rises and falls over time. The x-axisrepresents time; the y-axis represents current in picoAmps. As depictedon the legend, the small diamond points represent the current measuredfrom the working electrode. The time-corresponding blood glucose valuesshow the correlation of the sensor data to the blood glucose data,indicating appropriate tracking of glucose concentration over time.

FIG. 28B is a graphical representation showing transcutaneous glucosesensor data and corresponding blood glucose values over time in a human.The x-axis represents time; the y-axis represents glucose concentrationin mg/dL. As depicted on the legend, the small diamond points representthe calibrated glucose data measured from a transcutaneous glucosesensor of a preferred embodiment; while the larger points representblood glucose values of blood withdrawn from a finger stick and analyzedusing an in vitro self-monitoring blood glucose meter. The calibratedglucose data corresponds to the data of FIG. 28A shown in current,except it has been calibrated using algorithms of the preferredembodiments. Accordingly, accurate transcutaneous measurement of glucoseconcentration has been obtained and processed using the systems andmethods of the preferred embodiments.

Example 4

The sensors of preferred embodiments are configured to work within lowoxygen environments. Performance of a transcutaneous sensor, built inaccordance with the preferred embodiments, was investigated at variousoxygen concentrations. The investigation was conducted by measuringfunctionality of the sensor in a solution of 400 mg/dL glucose atdifferent O₂ concentrations. Functionality of the sensor is shown by asignal generated when the sensor is placed in 400 mg/dL glucose solutionat ambient O₂ concentration, which is used to set 100% performance ofthe glucose sensor. Good performance, defined as a 100±10%functionality, was observed over oxygen concentrations of from about0.02 mg/L up to about 1.0 mg/L O₂ concentrations. In other words, thetranscutaneous sensor exhibited 100% (+/−10%) functionality in anenvironment having an oxygen concentration as low as about 0.02 mg/L O₂(the detection limit of the measurement). A plot of functionality versus[O₂] in mg/L for a representative sensor tested is provided in FIG. 29.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. No.4,994,167 issued Feb. 19, 1991 and entitled “BIOLOGICAL FLUID MEASURINGDEVICE”; U.S. Pat. No. 4,757,022 issued February Jul. 12, 1988 andentitled “BIOLOGICAL FLUID MEASURING DEVICE”; U.S. Pat. No. 6,001,067issued February Dec. 14, 1999 and entitled “DEVICE AND METHOD FORDETERMINING ANALYTE LEVELS”; U.S. Pat. No. 6,741,877 issued February May25, 2004 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTELEVELS”; U.S. Pat. No. 6,702,857 issued February Mar. 9, 2004 andentitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”; and U.S. Pat. No.6,558,321 issued February May 6, 2003 and entitled “SYSTEMS AND METHODSFOR REMOTE MONITORING AND MODULATION OF MEDICAL DEVICES.” Methods anddevices that are suitable for use in conjunction with aspects of thepreferred embodiments are disclosed in co-pending U.S. application Ser.No. 10/991,353 filed Nov. 16, 2004 and entitled “AFFINITY DOMAIN FORANALYTE SENSOR”; U.S. application Ser. No. 11/055,779 filed Feb. 9, 2005and entitled “BIOINTERFACE WITH MACRO-AND-MICRO-ARCHITECTURE”; U.S.application Ser. No. 11/004,561 filed Dec. 3, 2004 and entitled“CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR”; U.S.application Ser. No. 11/034,343 filed Jan. 11, 2005 and entitled“COMPOSITE MATERIAL FOR IMPLANTABLE DEVICE”; U.S. application Ser. No.09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHOD FORDETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/021,046 filedDec. 22, 2004 and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTELEVELS”; U.S. application Ser. No. 09/916,858 filed Jul. 27, 2001 andentitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S.application Ser. No. 11/039,269 filed Jan. 19, 2005 and entitled “DEVICEAND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No.10/897,377 filed Jul. 21, 2004 and entitled “ELECTROCHEMICAL SENSORSINCLUDING ELECTRODE SYSTEMS WITH INCREASED OXYGEN GENERATION”; U.S.application Ser. No. 10/897,312 filed Jul. 21, 2004 and entitled“ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS”; U.S. application Ser.No. 10/838,912 filed May 3, 2004 and entitled “IMPLANTABLE ANALYTESENSOR”; U.S. application Ser. No. 10/838,909 filed May 3, 2004 andentitled “IMPLANTABLE ANALYTE SENSOR”; U.S. application Ser. No.10/838,658 filed May 3, 2004 and entitled “IMPLANTABLE ANALYTE SENSOR”;U.S. application Ser. No. 11/034,344 filed Jan. 11, 2005 and entitled“IMPLANTABLE DEVICE WITH IMPROVED RADIO FREQUENCY CAPABILITIES”; U.S.application Ser. No. 10/896,772 filed Jul. 21, 2004 and entitled“INCREASING BIAS FOR OXYGEN PRODUCTION IN AN ELECTRODE SYSTEM”; U.S.application Ser. No. 10/789,359 filed Feb. 26, 2004 and entitled“INTEGRATED DELIVERY DEVICE FOR CONTINUOUS GLUCOSE SENSOR”; U.S.application Ser. No. 10/991,966 filed Nov. 17, 2004 and entitled“INTEGRATED RECEIVER FOR CONTINUOUS ANALYTE SENSOR”; U.S. applicationSer. No. 10/646,333 filed Aug. 22, 2003 and entitled “OPTIMIZED SENSORGEOMETRY FOR AN IMPLANTABLE GLUCOSE SENSOR”; U.S. application Ser. No.10/896,639 filed Jul. 21, 2004 and entitled “OXYGEN ENHANCING MEMBRANESYSTEMS FOR IMPLANTABLE DEVICES”; U.S. application Ser. No. 10/647,065filed Aug. 22, 2003 and entitled “POROUS MEMBRANES FOR USE WITHIMPLANTABLE DEVICES”; U.S. application Ser. No. 10/896,637 filed Jul.21, 2004 and entitled “ROLLED ELECTRODE ARRAY AND ITS METHOD FORMANUFACTURE”; U.S. application Ser. No. 09/916,711 filed Jul. 27, 2001and entitled “SENSOR HEAD FOR USE WITH IMPLANTABLE DEVICE”; U.S.application Ser. No. 11/021,162 filed Dec. 22, 2004 and entitled “SENSORHEAD FOR USE WITH IMPLANTABLE DEVICES”; U.S. application Ser. No.11/007,920 filed Dec. 8, 2004 and entitled “SIGNAL PROCESSING FORCONTINUOUS ANALYTE SENSOR”; U.S. application Ser. No. 10/695,636 filedOct. 28, 2003 and entitled “SILICONE COMPOSITION FOR BIOCOMPATIBLEMEMBRANE”; U.S. application Ser. No. 11/038,340 filed Jan. 18, 2005 andentitled “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S.application Ser. No. 11/007,635 filed Dec. 7, 2004 and entitled “SYSTEMSAND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS”; U.S.application Ser. No. 10/885,476 filed Jul. 6, 2004 and entitled “SYSTEMSAND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING AMEMBRANE SYSTEM”; U.S. application Ser. No. 10/648,849 filed Aug. 22,2003 and entitled “SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS INA GLUCOSE SENSOR DATA STREAM”; U.S. application Ser. No. 10/153,356filed May 22, 2002 and entitled “TECHNIQUES TO IMPROVE POLYURETHANEMEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No.10/846,150 filed May 14, 2004 and entitled “ANALYTE MEASURING DEVICE”;U.S. application Ser. No. 10/842,716 filed May 10, 2004 and entitled“BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS”; U.S.application Ser. No. 10/657,843 filed Sep. 9, 2003 and entitled “DEVICEAND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No.10/768,889 filed Jan. 29, 2004 and entitled “MEMBRANE FOR USE WITHIMPLANTABLE DEVICES”; U.S. application Ser. No. 10/633,367 filed Aug. 1,2003 and entitled “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSORDATA”; U.S. application Ser. No. 10/632,537 filed Aug. 1, 2003 andentitled “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S.application Ser. No. 10/633,404 filed Aug. 1, 2003 and entitled “SYSTEMAND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. application Ser.No. 10/633,329 filed Aug. 1, 2003 and entitled “SYSTEM AND METHODS FORPROCESSING ANALYTE SENSOR DATA”; U.S. application Ser. No. 11/077,715filed on Mar. 10, 2005 entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S.application Ser. No. 11/077,883 filed on Mar. 10, 2005 entitled“TRANSCUTANEOUS ANALYTE SENSOR”; U.S. application Ser. No. 11/078,230filed on Mar. 10, 2005 entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S.application Ser. No. 11/078,232 filed on Mar. 10, 2005 entitled“TRANSCUTANEOUS ANALYTE SENSOR”; U.S. application Ser. No. 11/077,713filed on Mar. 10, 2005 entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S.application Ser. No. 11/077,693 filed on Mar. 10, 2005 entitled“TRANSCUTANEOUS ANALYTE SENSOR”; U.S. application Ser. 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All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

What is claimed is:
 1. A transcutaneous glucose monitoring systemcomprising: an in vivo portion and an ex vivo portion; wherein the invivo portion comprises: an implantable body comprising an electrodeconfigured to measure a glucose level in a host; a membrane disposedover the electrode and configured to limit transport of glucose to theelectrode, wherein the membrane comprises polyurethaneurea, wherein themembrane is configured to provide the system with substantial linearityat glucose concentration of up to 400 mg/dL at an oxygen concentrationof 0.45 mg/L; a layer comprising an enzyme configured to catalyze areaction of glucose and oxygen from a biological fluid surrounding themembrane; and wherein the ex vivo portion comprises a sensor electronicsunit operably connected to the electrode and configured to measure acurrent produced by the electrode.
 2. The transcutaneous glucosemonitoring system of claim 1, wherein the sensor electronics unit isconfigured to directly measure the current produced by the electrode. 3.The transcutaneous glucose monitoring system of claim 1, furthercomprising a biointerface membrane configured to support tissueingrowth.
 4. The transcutaneous glucose monitoring system of claim 1,further comprising an analog-to-digital converter configured totranslate the current into a digital signal.
 5. The transcutaneousglucose monitoring system of claim 1, wherein the electrode comprises anexposed electroactive working electrode surface with a surface area offrom about 0.00002 in² to about 0.0079 in².
 6. The transcutaneousglucose monitoring system of claim 1, wherein the membrane comprises aresistance domain configured to have a permeability ratio of at leastabout 50:1 of glucose to an interferant.
 7. The transcutaneous glucosemonitoring system of claim 1, wherein the membrane comprises aresistance domain configured to have a permeability ratio of at leastabout 200:1 of glucose to an interferant.
 8. The transcutaneous glucosemonitoring system of claim 1, wherein the sensor system is configured tohave, in operation, a sensitivity of from about 1 pA/mg/dL to about 100pA/mg/dL.
 9. The transcutaneous glucose monitoring system of claim 1,wherein the sensor system is configured to have, in operation, asensitivity of from about 5 pA/mg/dL to about 25 pA/mg/dL.
 10. Thetranscutaneous glucose monitoring system of claim 1, wherein the sensorsystem is configured to have, in operation, a sensitivity of from about3.5 to about 7.5 pA/mg/dL.
 11. The transcutaneous glucose monitoringsystem of claim 1, wherein the sensor electronics unit is configured tomeasure glucose at an oxygen concentration of less than about 0.3 mg/L.12. The transcutaneous glucose monitoring system of claim 1, wherein thesensor electronics unit is configured to measure glucose at an oxygenconcentration of less than about 0.15 mg/L.
 13. The transcutaneousglucose monitoring system of claim 1, wherein the sensor electronicsunit is configured to measure glucose at an oxygen concentration of lessthan about 0.05 mg/L.
 14. The transcutaneous glucose monitoring systemof claim 1, wherein the sensor electronics unit is configured to measureglucose at an oxygen concentration of less than about 0.02 mg/L.
 15. Thetranscutaneous glucose monitoring system of claim 1, wherein themembrane is configured to provide the system with substantial linearityat glucose concentration of up to 400 mg/dL at oxygen concentration of0.4 mg/L.
 16. The transcutaneous glucose monitoring system of claim 1,wherein the membrane is configured to provide the system withsubstantial linearity at glucose concentration of up to 400 mg/dL atoxygen concentration of 0.3 mg/L.
 17. The transcutaneous glucosemonitoring system of claim 1, wherein the membrane is configured toprovide the system with substantial linearity at glucose concentrationof up to 400 mg/dL at oxygen concentration of 0.2 mg/L.
 18. Thetranscutaneous glucose monitoring system of claim 1, wherein the ex vivoportion further comprises a mounting unit adhered to a skin of the host,wherein the implantable body is configured to extend from inside a bodyof the host to the mounting unit.